TY  - JOUR
A1  - Yadav, Heena
A1  - Dreher, Dorothée
A1  - Athmer, Benedikt
A1  - Porzel, Andrea
A1  - Gavrin, Aleksandr
A1  - Baldermann, Susanne
A1  - Tissier, Alain
A1  - Hause, Bettina
T1  - Medicago TERPENE SYNTHASE 10 is involved in defense against an oomycete root pathogen
JF  - Plant physiology : an international journal devoted to physiology, biochemistry, cellular and molecular biology, biophysics and environmental biology of plants
N2  - In nature, plants interact with numerous beneficial or pathogenic soil-borne microorganisms. Plants have developed various defense strategies to expel pathogenic microbes, some of which function soon after pathogen infection. We used Medicago truncatula and its oomycete pathogen Aphanomyces euteiches to elucidate early responses of the infected root. A. euteiches causes root rot disease in legumes and is a limiting factor in legume production. Transcript profiling of seedlings and adult plant roots inoculated with A. euteiches zoospores for 2 h revealed specific upregulation of a gene encoding a putative sesquiterpene synthase (M. truncatula TERPENE SYNTHASE 10 [MtTPS10]) in both developmental stages. MtTPS10 was specifically expressed in roots upon oomycete infection. Heterologous expression of MtTPS10 in yeast led to production of a blend of sesquiterpenes and sesquiterpene alcohols, with NMR identifying a major peak corresponding to himalachol. Moreover, plants carrying a tobacco (Nicotiana tabacum) retrotransposon Tnt1 insertion in MtTPS10 lacked the emission of sesquiterpenes upon A. euteiches infection, supporting the assumption that the identified gene encodes a multiproduct sesquiterpene synthase. Mttps10 plants and plants with reduced MtTPS10 transcript levels created by expression of an MtTPS10-artificial microRNA in roots were more susceptible to A. euteiches infection than were the corresponding wild-type plants and roots transformed with the empty vector, respectively. Sesquiterpenes produced by expression of MtTPS10 in yeast also inhibited mycelial growth and A. euteiches zoospore germination. These data suggest that sesquiterpene production in roots by MtTPS10 plays a previously unrecognized role in the defense response of M. truncatula against A. euteiches.
Y1  - 2019
U6  - https://doi.org/10.1104/pp.19.00278
SN  - 0032-0889
SN  - 1532-2548
VL  - 180
IS  - 3
SP  - 1598
EP  - 1613
PB  - American Society of Plant Physiologists
CY  - Rockville
ER  - 
TY  - JOUR
A1  - Jonas, Wenke
A1  - Kluth, Oliver
A1  - Helms, Anett
A1  - Voss, Sarah
A1  - Jahnert, Markus
A1  - Gottmann, Pascal
A1  - Speckmann, Thilo
A1  - Knebel, Birgit
A1  - Chadt, Alexandra
A1  - Al-Hasani, Hadi
A1  - Schürmann, Annette
A1  - Vogel, Heike
T1  - Identification of novel genes involved in hyperglycemia in mice
JF  - International journal of molecular sciences
N2  - Current attempts to prevent and manage type 2 diabetes have been moderately effective, and a better understanding of the molecular roots of this complex disease is important to develop more successful and precise treatment options. 
Recently, we initiated the collective diabetes cross, where four mouse inbred strains differing in their diabetes susceptibility were crossed with the obese and diabetes-prone NZO strain and identified the quantitative trait loci (QTL) Nidd13/NZO, a genomic region on chromosome 13 that correlates with hyperglycemia in NZO allele carriers compared to B6 controls. 
Subsequent analysis of the critical region, harboring 644 genes, included expression studies in pancreatic islets of congenic Nidd13/NZO mice, integration of single-cell data from parental NZO and B6 islets as well as haplotype analysis. 
Finally, of the five genes (Acot12, S100z, Ankrd55, Rnf180, and Iqgap2) within the polymorphic haplotype block that are differently expressed in islets of B6 compared to NZO mice, we identified the calcium-binding protein S100z gene to affect islet cell proliferation as well as apoptosis when overexpressed in MINE cells. In summary, we define S100z as the most striking gene to be causal for the diabetes QTL Nidd13/NZO by affecting beta-cell proliferation and apoptosis. Thus, S100z is an entirely novel diabetes gene regulating islet cell function.
KW  - beta-cell
KW  - diabetes
KW  - proliferation
KW  - apoptosis
KW  - QTL
Y1  - 2022
U6  - https://doi.org/10.3390/ijms23063205
SN  - 1661-6596
SN  - 1422-0067
VL  - 23
IS  - 6
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Fayyaz, Susann
A1  - Japtok, Lukasz
A1  - Schumacher, Fabian
A1  - Wigger, Dominik
A1  - Schulz, Tim Julius
A1  - Haubold, Kathrin
A1  - Gulbins, Erich
A1  - Völler, Heinz
A1  - Kleuser, Burkhard
T1  - Lysophosphatidic acid inhibits insulin signaling in primary rat hepatocytes via the LPA(3) receptor subtype and is increased in obesity
JF  - Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry and pharmacology
N2  - Background/Aims:
Obesity is a main risk factor for the development of hepatic insulin resistance and it is accompanied by adipocyte hypertrophy and an elevated expression of different adipokines such as autotaxin (ATX). ATX converts lysophosphatidylcholine to lysophosphatidic acid (LPA) and acts as the main producer of extracellular LPA. This bioactive lipid regulates a broad range of physiological and pathological responses by activation of LPA receptors (LPA1-6).
Methods:
The activation of phosphatidylinositide 3-kinases (PI3K) signaling (Akt and GSK-3ß) was analyzed via western blotting in primary rat hepatocytes. Incorporation of glucose into glycogen was measured by using radio labeled glucose. Real-time PCR analysis and pharmacological modulation of LPA receptors were performed. Human plasma LPA levels of obese (BMI > 30, n = 18) and normal weight individuals (BMI 18.5-25, n = 14) were analyzed by liquid chromatography tandem-mass spectrometry (LC-MS/MS).
Results:
Pretreatment of primary hepatocytes with LPA resulted in an inhibition of insulin-mediated Gck expression, PI3K activation and glycogen synthesis. Pharmacological approaches revealed that the LPA3-receptor subtype is responsible for the inhibitory effect of LPA on insulin signaling. Moreover, human plasma LPA concentrations (16: 0 LPA) of obese participants (BMI > 30) are significantly elevated in comparison to normal weight individuals (BMI 18.5-25).
Conclusion:
LPA is able to interrupt insulin signaling in primary rat hepatocytes via the LPA3 receptor subtype. Moreover, the bioactive lipid LPA (16: 0) is increased in obesity.
KW  - Lysophosphatidic acid
KW  - Insulin signaling
KW  - Adipose tissue
KW  - Autotaxin
KW  - Hepatic insulin resistance
KW  - LPA(3) receptor subtype
Y1  - 2017
U6  - https://doi.org/10.1159/000480470
SN  - 1015-8987
SN  - 1421-9778
VL  - 43
SP  - 445
EP  - 456
PB  - Karger
CY  - Basel
ER  - 
TY  - JOUR
A1  - Wigger, Dominik
A1  - Schumacher, Fabian
A1  - Schneider-Schaulies, Sibylle
A1  - Kleuser, Burkhard
T1  - Sphingosine 1-phosphate metabolism and insulin signaling
JF  - Cellular signalling
N2  - Insulin is the main anabolic hormone secreted by 13-cells of the pancreas stimulating the assimilation and storage of glucose in muscle and fat cells. It modulates the postprandial balance of carbohydrates, lipids and proteins via enhancing lipogenesis, glycogen and protein synthesis and suppressing glucose generation and its release from the liver. Resistance to insulin is a severe metabolic disorder related to a diminished response of peripheral tissues to the insulin action and signaling. This leads to a disturbed glucose homeostasis that precedes the onset of type 2 diabetes (T2D), a disease reaching epidemic proportions. A large number of studies reported an association between elevated circulating fatty acids and the development of insulin resistance. The increased fatty acid lipid flux results in the accumulation of lipid droplets in a variety of tissues. However, lipid intermediates such as diacylglycerols and ceramides are also formed in response to elevated fatty acid levels. These bioactive lipids have been associated with the pathogenesis of insulin resistance. More recently, sphingosine 1-phosphate (S1P), another bioactive sphingolipid derivative, has also been shown to increase in T2D and obesity. Although many studies propose a protective role of S1P metabolism on insulin signaling in peripheral tissues, other studies suggest a causal role of S1P on insulin resistance. In this review, we critically summarize the current state of knowledge of S1P metabolism and its modulating role on insulin resistance. A particular emphasis is placed on S1P and insulin signaling in hepatocytes, skeletal muscle cells, adipocytes and pancreatic 13-cells. In particular, modulation of receptors and enzymes that regulate S1P metabolism can be considered as a new therapeutic option for the treatment of insulin resistance and T2D.
KW  - Insulin resistance
KW  - Type 2 diabetes
KW  - Sphingolipids
KW  - Hepatocytes
KW  - Adipocytes
KW  - Skeletal muscle cells
Y1  - 2021
U6  - https://doi.org/10.1016/j.cellsig.2021.109959
SN  - 0898-6568
SN  - 1873-3913
VL  - 82
PB  - Elsevier Science
CY  - Amsterdam [u.a.]
ER  - 
TY  - JOUR
A1  - Zoicas, Iulia
A1  - Schumacher, Fabian
A1  - Kleuser, Burkhard
A1  - Reichel, Martin
A1  - Gulbins, Erich
A1  - Fejtova, Anna
A1  - Kornhuber, Johannes
A1  - Rhein, Cosima
T1  - The forebrain-specific overexpression of acid sphingomyelinase induces depressive-like symptoms in mice
JF  - Cells
N2  - Human and murine studies identified the lysosomal enzyme acid sphingomyelinase (ASM) as a target for antidepressant therapy and revealed its role in the pathophysiology of major depression. In this study, we generated a mouse model with overexpression of Asm (Asm-tg(fb)) that is restricted to the forebrain to rule out any systemic effects of Asm overexpression on depressive-like symptoms. The increase in Asm activity was higher in male Asm-tg(fb) mice than in female Asm-tg(fb) mice due to the breeding strategy, which allows for the generation of wild-type littermates as appropriate controls. Asm overexpression in the forebrain of male mice resulted in a depressive-like phenotype, whereas in female mice, Asm overexpression resulted in a social anxiogenic-like phenotype. Ceramides in male Asm-tg(fb) mice were elevated specifically in the dorsal hippocampus. mRNA expression analyses indicated that the increase in Asm activity affected other ceramide-generating pathways, which might help to balance ceramide levels in cortical brain regions. This forebrain-specific mouse model offers a novel tool for dissecting the molecular mechanisms that play a role in the pathophysiology of major depression.
KW  - Smpd1
KW  - acid sphingomyelinase
KW  - forebrain
KW  - depressive-like behavior
KW  - anxiety-like behavior
KW  - ceramide
Y1  - 2020
VL  - 9
IS  - 5
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Wigger, Dominik
A1  - Gulbins, Erich
A1  - Kleuser, Burkhard
A1  - Schumacher, Fabian
T1  - Monitoring the Sphingolipid de novo Synthesis by Stable-Isotope Labeling and Liquid Chromatography-Mass Spectrometry
JF  - Frontiers in Cell and Developmental Biology
N2  - Sphingolipids are a class of lipids that share a sphingoid base backbone. They exert various effects in eukaryotes, ranging from structural roles in plasma membranes to cellular signaling. De novo sphingolipid synthesis takes place in the endoplasmic reticulum (ER), where the condensation of the activated C₁₆ fatty acid palmitoyl-CoA and the amino acid L-serine is catalyzed by serine palmitoyltransferase (SPT). The product, 3-ketosphinganine, is then converted into more complex sphingolipids by additional ER-bound enzymes, resulting in the formation of ceramides. Since sphingolipid homeostasis is crucial to numerous cellular functions, improved assessment of sphingolipid metabolism will be key to better understanding several human diseases. To date, no assay exists capable of monitoring de novo synthesis sphingolipid in its entirety. Here, we have established a cell-free assay utilizing rat liver microsomes containing all the enzymes necessary for bottom-up synthesis of ceramides. Following lipid extraction, we were able to track the different intermediates of the sphingolipid metabolism pathway, namely 3-ketosphinganine, sphinganine, dihydroceramide, and ceramide. This was achieved by chromatographic separation of sphingolipid metabolites followed by detection of their accurate mass and characteristic fragmentations through high-resolution mass spectrometry and tandem-mass spectrometry. We were able to distinguish, unequivocally, between de novo synthesized sphingolipids and intrinsic species, inevitably present in the microsome preparations, through the addition of stable isotope-labeled palmitate-d₃ and L-serine-d₃. To the best of our knowledge, this is the first demonstration of a method monitoring the entirety of ER-associated sphingolipid biosynthesis. Proof-of-concept data was provided by modulating the levels of supplied cofactors (e.g., NADPH) or the addition of specific enzyme inhibitors (e.g., fumonisin B₁). The presented microsomal assay may serve as a useful tool for monitoring alterations in sphingolipid de novo synthesis in cells or tissues. Additionally, our methodology may be used for metabolism studies of atypical substrates – naturally occurring or chemically tailored – as well as novel inhibitors of enzymes involved in sphingolipid de novo synthesis.
KW  - sphingolipid de novo synthesis
KW  - serine palmitoyltransferase
KW  - mass spectrometry
KW  - stable-isotope labeling
KW  - ceramides
Y1  - 2019
U6  - https://doi.org/10.3389/fcell.2019.00210
SN  - 2296-634X
VL  - 7
PB  - Frontiers Media
CY  - Lausanne
ER  - 
TY  - JOUR
A1  - Frombach, Janna
A1  - Unbehauen, Michael
A1  - Kurniasih, Indah N.
A1  - Schumacher, Fabian
A1  - Volz, Pierre
A1  - Hadam, Sabrina
A1  - Rancan, Fiorenza
A1  - Blume-Peytavi, Ulrike
A1  - Kleuser, Burkhard
A1  - Haag, Rainer
A1  - Alexiev, Ulrike
A1  - Vogt, Annika
T1  - Core-multishell nanocarriers enhance drug penetration and reach keratinocytes and antigen-presenting cells in intact human skin
JF  - Journal of controlled release
N2  - In reconstructed skin and diffusion cell studies, core-multishell nanocarriers (CMS-NC) showed great potential for drug delivery across the skin barrier. Herein, we investigated penetration, release of dexamethasone (DXM), in excised full-thickness human skin with special focus on hair follicles (HF). Four hours and 16 h after topical application of clinically relevant dosages of 10 mu g DXM/cm(2) skin encapsulated in CMS-NC (12 nm diameter, 5.8% loading), presence of DXM in the tissue as assessed by fluorescence microscopy of anti-DXM-stained tissue sections as well as ELISA and HPLC-MS/MS in tissue extracts was enhanced compared to standard LAW-creme but lower compared to DXM aqueous/alcoholic solution. Such enhanced penetration compared to conventional cremes offers high potential for topical therapies, as recurrent applications of corticosteroid solutions face limitations with regard to tolerability and fast drainage. The findings encourage more detailed investigations on where and how the nanocarrier and drug dissociate within the skin and what other factors, e.g. thermodynamic activity, influence the penetration of this formulations. Microscopic studies on the spatial distribution within the skin revealed accumulation in HF and furrows accompanied by limited cellular uptake assessed by flow cytometry (up to 9% of total epidermal cells). FLIM clearly visualized the presence of CMS-NC in the viable epidermis and dermis. When exposed in situ a fraction of up to 25% CD1a(+) cells were found within the epidermal CMS-NC+ population compared to approximately 3% CD1a(+)/CMS-NC+ cells after in vitro exposure in short-term cultures of epidermal cell suspensions. The latter reflects the natural percentage of Langerhans cells (LC) in epidermis suspensions and indicated that CMS-NC were not preferentially internalized by one cell type. The increased CMS-NC+ LC proportion after exposure within the tissue is in accordance with the strategic suprabasal LC-localization. More specifically we postulate that the extensive dendrite meshwork, their position around HF orifices and their capacity to modulate tight junctions facilitated a preferential uptake of CMS-NC by LC within the skin. This newly identified aspect of CMS-NC penetration underlines the potential of CMS-NC for dermatotherapy and encourages further investigations of CMS-NC for the delivery of other molecule classes for which intracellular delivery is even more crucial.
KW  - Drug delivery
KW  - Skin penetration
KW  - Cellular uptake
KW  - Nanoparticles
KW  - Dendritic cells
KW  - High resolution microscopy
Y1  - 2019
U6  - https://doi.org/10.1016/j.jconrel.2019.02.028
SN  - 0168-3659
SN  - 1873-4995
VL  - 299
SP  - 138
EP  - 148
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Wiesner-Reinhold, Melanie
A1  - Barknowitz, Gitte
A1  - Florian, Simone
A1  - Mewis, Inga
A1  - Schumacher, Fabian
A1  - Schreiner, Monika
A1  - Glatt, Hansruedi
T1  - 1-Methoxy-3-indolylmethyl DNA adducts in six tissues, and blood protein adducts, in mice under pak choi diet: time course and persistence
JF  - Archives of toxicology : official journal of EUROTOX
N2  - We previously showed that purified 1-methoxy-3-indolylmethyl (1-MIM) glucosinolate, a secondary plant metabolite in Brassica species, is mutagenic in various in vitro systems and forms DNA and protein adducts in mouse models. In the present study, we administered 1-MIM glucosinolate in a natural matrix to mice, by feeding a diet containing pak choi powder and extract. Groups of animals were killed after 1, 2, 4 and 8 days of pak choi diet, directly or, in the case of the 8-day treatment, after 0, 8 and 16 days of recovery with pak choi-free diet. DNA adducts [N-2-(1-MIM)-dG, N-6-(1-MIM)-dA] in six tissues, as well as protein adducts [tau N-(1-MIM)-His] in serum albumin (SA) and hemoglobin (Hb) were determined using UPLC-MS/MS with isotopically labeled internal standards. None of the samples from the 12 control animals under standard diet contained any 1-MIM adducts. All groups receiving pak choi diet showed DNA adducts in all six tissues (exception: lung of mice treated for a single day) as well as SA and Hb adducts. During the feeding period, all adduct levels continuously increased until day 8 (in the jejunum until day 4). During the 14-day recovery period, N-2-(1-MIM)-dG in liver, kidney, lung, jejunum, cecum and colon decreased to 52, 41, 59, 11, 7 and 2%, respectively, of the peak level. The time course of N-6-(1-MIM)-dA was similar. Immunohistochemical analyses indicated that cell turnover is a major mechanism of DNA adduct elimination in the intestine. In the same recovery period, protein adducts decreased more rapidly in SA than in Hb, to 0.7 and 37%, respectively, of the peak level, consistent with the differential turnover of these proteins. In conclusion, the pak choi diet lead to the formation of high levels of adducts in mice. Cell and protein turnover was a major mechanism of adduct elimination, at least in gut and blood.
KW  - 1-Methoxy-3-indolylmethyl glucosinolate
KW  - Neoglucobrassicin
KW  - DNA adducts
KW  - Blood protein adducts
KW  - Pak choi
Y1  - 2019
U6  - https://doi.org/10.1007/s00204-019-02452-3
SN  - 0340-5761
SN  - 1432-0738
VL  - 93
IS  - 6
SP  - 1515
EP  - 1527
PB  - Springer
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Rancan, Fiorenza
A1  - Volkmann, Hildburg
A1  - Giulbudagian, Michael
A1  - Schumacher, Fabian
A1  - Stanko, Jessica Isolde
A1  - Kleuser, Burkhard
A1  - Blume-Peytavi, Ulrike
A1  - Calderon, Marcelo
A1  - Vogt, Annika
T1  - Dermal Delivery of the High-Molecular-Weight Drug Tacrolimus by Means of Polyglycerol-Based Nanogels
JF  - Pharmaceutics : Molecular Diversity Preservation International
N2  - Polyglycerol-based thermoresponsive nanogels (tNGs) have been shown to have excellent skin hydration properties and to be valuable delivery systems for sustained release of drugs into skin. In this study, we compared the skin penetration of tacrolimus formulated in tNGs with a commercial 0.1% tacrolimus ointment. The penetration of the drug was investigated in ex vivo abdominal and breast skin, while different methods for skin barrier disruption were investigated to improve skin permeability or simulate inflammatory conditions with compromised skin barrier. The amount of penetrated tacrolimus was measured in skin extracts by liquid chromatography tandem-mass spectrometry (LC-MS/MS), whereas the inflammatory markers IL-6 and IL-8 were detected by enzyme-linked immunosorbent assay (ELISA). Higher amounts of tacrolimus penetrated in breast as compared to abdominal skin or in barrier-disrupted as compared to intact skin, confirming that the stratum corneum is the main barrier for tacrolimus skin penetration. The anti-proliferative effect of the penetrated drug was measured in skin tissue/Jurkat cells co-cultures. Interestingly, tNGs exhibited similar anti-proliferative effects as the 0.1% tacrolimus ointment. We conclude that polyglycerol-based nanogels represent an interesting alternative to paraffin-based formulations for the treatment of inflammatory skin conditions.
KW  - tacrolimus formulation
KW  - nanogels
KW  - skin penetration
KW  - drug delivery
KW  - human excised skin
KW  - Jurkat cells
Y1  - 2019
U6  - https://doi.org/10.3390/pharmaceutics11080394
SN  - 1999-4923
VL  - 11
IS  - 8
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Laeger, Thomas
A1  - Castano-Martinez, Teresa
A1  - Werno, Martin W.
A1  - Japtok, Lukasz
A1  - Baumeier, Christian
A1  - Jonas, Wenke
A1  - Kleuser, Burkhard
A1  - Schürmann, Annette
T1  - Dietary carbohydrates impair the protective effect of protein restriction against diabetes in NZO mice used as a model of type 2 diabetes
JF  - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
N2  - Aims/hypothesis Low-protein diets are well known to improve glucose tolerance and increase energy expenditure. Increases in circulating fibroblast growth factor 21 (FGF21) have been implicated as a potential underlying mechanism. Methods We aimed to test whether low-protein diets in the context of a high-carbohydrate or high-fat regimen would also protect against type 2 diabetes in New Zealand Obese (NZO) mice used as a model of polygenetic obesity and type 2 diabetes. Mice were placed on high-fat diets that provided protein at control (16 kJ%; CON) or low (4 kJ%; low-protein/high-carbohydrate [LP/HC] or low-protein/high-fat [LP/HF]) levels. Results Protein restriction prevented the onset of hyperglycaemia and beta cell loss despite increased food intake and fat mass. The effect was seen only under conditions of a lower carbohydrate/fat ratio (LP/HF). When the carbohydrate/fat ratio was high (LP/HC), mice developed type 2 diabetes despite the robustly elevated hepatic FGF21 secretion and increased energy expenditure. Conclusion/interpretation Prevention of type 2 diabetes through protein restriction, without lowering food intake and body fat mass, is compromised by high dietary carbohydrates. Increased FGF21 levels and elevated energy expenditure do not protect against hyperglycaemia and type 2 diabetes per se.
KW  - Energy expenditure
KW  - FGF21
KW  - Hyperglycaemia
KW  - Insulin resistance
KW  - NZO
KW  - Obesity
KW  - Protein restriction
Y1  - 2018
U6  - https://doi.org/10.1007/s00125-018-4595-1
SN  - 0012-186X
SN  - 1432-0428
VL  - 61
IS  - 6
SP  - 1459
EP  - 1469
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - McVey, Mark J.
A1  - Kim, Michael
A1  - Tabuchi, Arata
A1  - Srbely, Victoria
A1  - Japtok, Lukasz
A1  - Arenz, Christoph
A1  - Rotstein, Ori
A1  - Kleuser, Burkhard
A1  - Semple, John W.
A1  - Kuebler, Wolfgang M.
T1  - Acid sphingomyelinase mediates murine acute lung injury following transfusion of aged platelets
JF  - American journal of physiology : Lung cellular and molecular physiology
N2  - Pulmonary complications from stored blood products are the leading cause of mortality related to transfusion. Transfusion-related acute lung injury is mediated by antibodies or bioactive mediators, yet underlying mechanisms are incompletely understood. Sphingolipids such as ceramide regulate lung injury, and their composition changes as a function of time in stored blood. Here, we tested the hypothesis that aged platelets may induce lung injury via a sphingolipid-mediated mechanism. To assess this hypothesis, a two-hit mouse model was devised. Recipient mice were treated with 2 mg/kg intraperitoneal lipopolysaccharide (priming) 2 h before transfusion of 10 ml/kg stored (1-5 days) platelets treated with or without addition of acid sphingomyelinase inhibitor ARC39 or platelets from acid sphingomyelinase-deficient mice, which both reduce ceramide formation. Transfused mice were examined for signs of pulmonary neutrophil accumulation, endothelial barrier dysfunction, and histological evidence of lung injury. Sphingolipid profiles in stored platelets were analyzed by mass spectrophotometry. Transfusion of aged platelets into primed mice induced characteristic features of lung injury, which increased in severity as a function of storage time. Ceramide accumulated in platelets during storage, but this was attenuated by ARC39 or in acid sphingomyelinase-deficient platelets. Compared with wild-type platelets, transfusion of ARC39-treated or acid sphingomyelinase-deficient aged platelets alleviated lung injury. Aged platelets elicit lung injury in primed recipient mice, which can be alleviated by pharmacological inhibition or genetic deletion of acid sphingomyelinase. Interventions targeting sphingolipid formation represent a promising strategy to increase the safety and longevity of stored blood products.
KW  - transfusion-related acute lung injury
KW  - ceramide
KW  - acid sphingomyelinase
KW  - platelets
KW  - storage
Y1  - 2017
U6  - https://doi.org/10.1152/ajplung.00317.2016
SN  - 1040-0605
SN  - 1522-1504
VL  - 312
IS  - 5
SP  - 625
EP  - 637
PB  - American Physiological Society
CY  - Bethesda
ER  - 
TY  - JOUR
A1  - Bernacchioni, Caterina
A1  - Ghini, Veronica
A1  - Cencetti, Francesca
A1  - Japtok, Lukasz
A1  - Donati, Chiara
A1  - Bruni, Paola
A1  - Turano, Paola
T1  - NMR metabolomics highlights sphingosine kinase-1 as a new molecular switch in the orchestration of aberrant metabolic phenotype in cancer cells
JF  - Molecular oncology / Federation of European Biochemical Societies
N2  - Strong experimental evidence in animal and cellular models supports a pivotal role of sphingosine kinase-1 (SK1) in oncogenesis. In many human cancers, SK1 levels are upregulated and these increases are linked to poor prognosis in patients. Here, by employing untargeted NMR- based metabolomic profiling combined with functional validations, we report the crucial role of SK1 in the metabolic shift known as the Warburg effect in A2780 ovarian cancer cells. Indeed, expression of SK1 induced a high glycolytic rate, characterized by increased levels of lactate along with increased expression of the proton/monocarboxylate symporter MCT1, and decreased oxidative metabolism, associated with the accumulation of intermediates of the tricarboxylic acid cycle and reduction in CO2 production. Additionally, SK1-expressing cells displayed a significant increase in glucose uptake paralleled by GLUT3 transporter upregulation. The role of SK1 is not limited to the induction of aerobic glycolysis, affecting metabolic pathways that appear to support the biosynthesis of macromolecules. These findings highlight the role of SK1 signaling axis in cancer metabolic reprogramming, pointing out innovative strategies for cancer therapies.
KW  - NMR-based metabolomics
KW  - ovarian cancer
KW  - sphingosine kinase-1
KW  - Warburg effect
Y1  - 2017
U6  - https://doi.org/10.1002/1878-0261.12048
SN  - 1878-0261
VL  - 11
SP  - 517
EP  - 533
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Hoehn, Richard S.
A1  - Jernigan, Peter L.
A1  - Japtok, Lukasz
A1  - Chang, Alex L.
A1  - Midura, Emily F.
A1  - Caldwell, Charles C.
A1  - Kleuser, Burkhard
A1  - Lentsch, Alex B.
A1  - Edwards, Michael J.
A1  - Gulbins, Erich
A1  - Pritts, Timothy A.
T1  - Acid sphingomyelinase inhibition in stored erythrocytes reduces transfusion-associated lung inflammation
JF  - Annals of surgery : a monthly review of surgical science and practice
N2  - Objective: We aimed to identify the role of the enzyme acid sphingomyelinase in the aging of stored units of packed red blood cells (pRBCs) and subsequent lung inflammation after transfusion.
Summary Background Data: Large volume pRBC transfusions are associated with multiple adverse clinical sequelae, including lung inflammation. Microparticles are formed in stored pRBCs over time and have been shown to contribute to lung inflammation after transfusion.
Methods: Human and murine pRBCs were stored with or without amitriptyline, a functional inhibitor of acid sphingomyelinase, or obtained from acid sphingomyelinase-deficient mice, and lung inflammation was studied in mice receiving transfusions of pRBCs and microparticles isolated from these units.
Results: Acid sphingomyelinase activity in pRBCs was associated with the formation of ceramide and the release of microparticles. Treatment of pRBCs with amitriptyline inhibited acid sphingomyelinase activity, ceramide accumulation, and microparticle production during pRBC storage. Transfusion of aged pRBCs or microparticles isolated from aged blood into mice caused lung inflammation. This was attenuated after transfusion of pRBCs treated with amitriptyline or from acid sphingomyelinase-deficient mice.
Conclusions: Acid sphingomyelinase inhibition in stored pRBCs offers a novel mechanism for improving the quality of stored blood.
KW  - acid sphingomyelinase
KW  - blood banking
KW  - ceramide
KW  - lung inflammation
KW  - microparticle
Y1  - 2017
U6  - https://doi.org/10.1097/SLA.0000000000001648
SN  - 0003-4932
SN  - 1528-1140
VL  - 265
IS  - 1
SP  - 218
EP  - 226
PB  - Lippincott Williams & Wilkins
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Folkesson, Maggie
A1  - Vorkapic, Emina
A1  - Gulbins, Erich
A1  - Japtok, Lukasz
A1  - Kleuser, Burkhard
A1  - Welander, Martin
A1  - Länne, Toste
A1  - Wågsäter, Dick
T1  - Inflammatory cells, ceramides, and expression of proteases in perivascular adipose tissue adjacent to human abdominal aortic aneurysms
JF  - Journal of vascular surgery
N2  - Background: Abdominal aortic aneurysm (AAA) is a deadly irreversible weakening and distension of the abdominal aortic wall. The pathogenesis of AAA remains poorly understood. Investigation into the physical and molecular characteristics of perivascular adipose tissue (PVAT) adjacent to AAA has not been done before and is the purpose of this study. 

Methods and Results: Human aortae, periaortic PVAT, and fat surrounding peripheral arteries were collected from patients undergoing elective surgical repair of AAA. Control aortas were obtained from recently deceased healthy organ donors with no known arterial disease. Aorta and PVAT was found in AAA to larger extent compared with control aortas. Immunohistochemistry revealed neutrophils, macrophages, mast cells, and T-cells surrounding necrotic adipocytes. Gene expression analysis showed that neutrophils, mast cells, and T-cells were found to be increased in PVAT compared with AAA as well as cathepsin K and S. The concentration of ceramides in PVAT was determined using mass spectrometry and correlated with content of T-cells in the PVAT. 

Conclusions: Our results suggest a role for abnormal necrotic, inflamed, proteolytic adipose tissue to the adjacent aneurysmal aortic wall in ongoing vascular damage.
Y1  - 2016
U6  - https://doi.org/10.1016/j.jvs.2015.12.056
SN  - 0741-5214
VL  - 65
IS  - 4
SP  - 1171
EP  - 1179
PB  - Elsevier
CY  - New York
ER  - 
TY  - JOUR
A1  - Dwi Putra, Sulistyo Emantoko
A1  - Reichetzeder, Christoph
A1  - Hasan, Ahmed Abdallah Abdalrahman Mohamed
A1  - Slowinski, Torsten
A1  - Chu, Chang
A1  - Krämer, Bernhard K.
A1  - Kleuser, Burkhard
A1  - Hocher, Berthold
T1  - Being born large for gestational age is associated with increased global placental DNA methylation
JF  - Scientific Reports
N2  - Being born small (SGA) or large for gestational age (LGA) is associated with adverse birth outcomes and metabolic diseases in later life of the offspring. It is known that aberrations in growth during gestation are related to altered placental function. Placental function is regulated by epigenetic mechanisms such as DNA methylation. Several studies in recent years have demonstrated associations between altered patterns of DNA methylation and adverse birth outcomes. However, larger studies that reliably investigated global DNA methylation are lacking. The aim of this study was to characterize global placental DNA methylation in relationship to size for gestational age. Global DNA methylation was assessed in 1023 placental samples by LC-MS/MS. LGA offspring displayed significantly higher global placental DNA methylation compared to appropriate for gestational age (AGA; p<0.001). ANCOVA analyses adjusted for known factors impacting on DNA methylation demonstrated an independent association between placental global DNA methylation and LGA births (p<0.001). Tertile stratification according to global placental DNA methylation levels revealed a significantly higher frequency of LGA births in the third tertile. Furthermore, a multiple logistic regression analysis corrected for known factors influencing birth weight highlighted an independent positive association between global placental DNA methylation and the frequency of LGA births (p=0.001).
KW  - fetal origins hypothesis
KW  - birth weight
KW  - repetitive elements
KW  - glucocorticoid receptor
KW  - nutrient transport
KW  - growth restriction
KW  - later health
KW  - pregnancy
KW  - genes
KW  - patterns
Y1  - 2020
U6  - https://doi.org/10.1038/s41598-020-57725-0
SN  - 2045-2322
VL  - 10
IS  - 1
SP  - 1
EP  - 10
PB  - Springer Nature
CY  - London
ER  - 
TY  - JOUR
A1  - Klaus, Susanne
A1  - Igual Gil, Carla
A1  - Ost, Mario
T1  - Regulation of diurnal energy balance by mitokines
JF  - Cellular and molecular life sciences : CMLS
N2  - The mammalian system of energy balance regulation is intrinsically rhythmic with diurnal oscillations of behavioral and metabolic traits according to the 24 h day/night cycle, driven by cellular circadian clocks and synchronized by environmental or internal cues such as metabolites and hormones associated with feeding rhythms. Mitochondria are crucial organelles for cellular energy generation and their biology is largely under the control of the circadian system. Whether mitochondrial status might also feed-back on the circadian system, possibly via mitokines that are induced by mitochondrial stress as endocrine-acting molecules, remains poorly understood. Here, we describe our current understanding of the diurnal regulation of systemic energy balance, with focus on fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), two well-known endocrine-acting metabolic mediators. FGF21 shows a diurnal oscillation and directly affects the output of the brain master clock. Moreover, recent data demonstrated that mitochondrial stress-induced GDF15 promotes a day-time restricted anorexia and systemic metabolic remodeling as shown in UCP1-transgenic mice, where both FGF21 and GDF15 are induced as myomitokines. In this mouse model of slightly uncoupled skeletal muscle mitochondria GDF15 proved responsible for an increased metabolic flexibility and a number of beneficial metabolic adaptations. However, the molecular mechanisms underlying energy balance regulation by mitokines are just starting to emerge, and more data on diurnal patterns in mouse and man are required. This will open new perspectives into the diurnal nature of mitokines and action both in health and disease.
KW  - Mitochondria
KW  - FGF21
KW  - GDF15
KW  - Circadian rhythm
KW  - Hormones
KW  - Nutrition
Y1  - 2021
U6  - https://doi.org/10.1007/s00018-020-03748-9
SN  - 1420-682X
SN  - 1420-9071
VL  - 78
IS  - 7
SP  - 3369
EP  - 3384
PB  - Springer International Publishing AG
CY  - Cham (ZG)
ER  - 
TY  - JOUR
A1  - McNulty, Margaret A.
A1  - Goupil, Brad A.
A1  - Albarado, Diana C.
A1  - Castaño-Martinez, Teresa
A1  - Ambrosi, Thomas H.
A1  - Puh, Spela
A1  - Schulz, Tim Julius
A1  - Schürmann, Annette
A1  - Morrison, Christopher D.
A1  - Laeger, Thomas
T1  - FGF21, not GCN2, influences bone morphology due to dietary protein restrictions
JF  - Bone Reports
N2  - Background: Dietary protein restriction is emerging as an alternative approach to treat obesity and glucose intolerance because it markedly increases plasma fibroblast growth factor 21 (FGF21) concentrations. Similarly, dietary restriction of methionine is known to mimic metabolic effects of energy and protein restriction with FGF21 as a required mechanism. However, dietary protein has been shown to be required for normal bone growth, though there is conflicting evidence as to the influence of dietary protein restriction on bone remodeling. The purpose of the current study was to evaluate the effect of dietary protein and methionine restriction on bone in lean and obese mice, and clarify whether FGF21 and general control nonderepressible 2 (GCN2) kinase, that are part of a novel endocrine pathway implicated in the detection of protein restriction, influence the effect of dietary protein restriction on bone.

Methods: Adult wild-type (WT) or Fgf21 KO mice were fed a normal protein (18 kcal%; CON) or low protein (4 kcal%; LP) diet for 2 or 27 weeks. In addition, adult WT or Gcn2 KO mice were fed a CON or LP diet for 27 weeks. Young New Zealand obese (NZO) mice were placed on high-fat diets that provided protein at control (16 kcal%; CON), low levels (4 kcal%) in a high-carbohydrate (LP/HC) or high-fat (LP/HF) regimen, or on high-fat diets (protein, 16 kcal%) that provided methionine at control (0.86%; CON-MR) or low levels (0.17%; MR) for up to 9 weeks. Long bones from the hind limbs of these mice were collected and evaluated with micro-computed tomography (mu CT) for changes in trabecular and cortical architecture and mass.

Results: In WT mice the 27-week LP diet significantly reduced cortical bone, and this effect was enhanced by deletion of Fgf21 but not Gcn2. This decrease in bone did not appear after 2 weeks on the LP diet. In addition, Fgf21 KO mice had significantly less bone than their WT counterparts. In obese NZO mice dietary protein and methionine restriction altered bone architecture. The changes were mediated by FGF21 due to methionine restriction in the presence of cystine, which did not increase plasma FGF21 levels and did not affect bone architecture.

Conclusions: This study provides direct evidence of a reduction in bone following long-term dietary protein restriction in a mouse model, effects that appear to be mediated by FGF21.
KW  - dietary restriction
KW  - protein restriction
KW  - FGF21
KW  - GCN2
KW  - microcomputed tomography
Y1  - 2020
U6  - https://doi.org/10.1016/j.bonr.2019.100241
SN  - 2352-1872
VL  - 12
SP  - 1
EP  - 10
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Schjeide, Brit-Maren
A1  - Schenke, Maren
A1  - Seeger, Bettina
A1  - Püschel, Gerhard
T1  - Validation of a novel double control quantitative copy number PCR method to quantify off-target transgene integration after CRISPR-induced DNA modification
JF  - Methods and protocols : M&Ps
N2  - In order to improve a recently established cell-based assay to assess the potency of botulinum neurotoxin, neuroblastoma-derived SiMa cells and induced pluripotent stem-cells (iPSC) were modified to incorporate the coding sequence of a reporter luciferase into a genetic safe harbor utilizing CRISPR/Cas9. A novel method, the double-control quantitative copy number PCR (dc-qcnPCR), was developed to detect off-target integrations of donor DNA. The donor DNA insertion success rate and targeted insertion success rate were analyzed in clones of each cell type. The dc-qcnPCR reliably quantified the copy number in both cell lines. The probability of incorrect donor DNA integration was significantly increased in SiMa cells in comparison to the iPSCs. This can possibly be explained by the lower bundled relative gene expression of a number of double-strand repair genes (BRCA1, DNA2, EXO1, MCPH1, MRE11, and RAD51) in SiMa clones than in iPSC clones. The dc-qcnPCR offers an efficient and cost-effective method to detect off-target CRISPR/Cas9-induced donor DNA integrations.
KW  - CRISPR editing validation
KW  - copy number analyses
KW  - homology-directed repair
KW  - homologous recombination deficiency
Y1  - 2022
U6  - https://doi.org/10.3390/mps5030043
SN  - 2409-9279
VL  - 5
IS  - 3
SP  - 1
EP  - 14
PB  - MDPI
CY  - Basel, Schweiz
ER  - 
TY  - JOUR
A1  - Rund, Katharina M.
A1  - Heylmann, Daniel
A1  - Seiwert, Nina
A1  - Wecklein, Sabine
A1  - Oger, Camille
A1  - Galano, Jean-Marie
A1  - Durand, Thierry
A1  - Chen, Rongjun
A1  - Güler, Faikah
A1  - Fahrer, Jörg
A1  - Bornhorst, Julia
A1  - Schebb, Nils Helge
T1  - Formation of trans-epoxy fatty acids correlates with formation of isoprostanes and could serve as biomarker of oxidative stress
JF  - Prostaglandins & Other Lipid Mediators
N2  - In mammals, epoxy-polyunsaturated fatty acids (epoxy-PUFA) are enzymatically formed from naturally occurring all-cis PUFA by cytochrome P450 monooxygenases leading to the generation of cis-epoxy-PUFA (mixture of R,S- and S,R-enantiomers). In addition, also non-enzymatic chemical peroxidation gives rise to epoxy-PUFA leading to both, cis- and trans-epoxy-PUFA (mixture of R,R- and S,S-enantiomers). Here, we investigated for the first time trans-epoxy-PUFA and the trans/cis-epoxy-PUFA ratio as potential new biomarker of lipid peroxidation. Their formation was analyzed in correlation with the formation of isoprostanes (IsoP), which are commonly used as biomarkers of oxidative stress. Five oxidative stress models were investigated including incubations of three human cell lines as well as the in vivo model Caenorhabditis elegans with tert-butyl hydroperoxide (t-BOOH) and analysis of murine kidney tissue after renal ischemia reperfusion injury (IRI). A comprehensive set of IsoP and epoxy-PUFA derived from biologically relevant PUFA (ARA, EPA and DHA) was simultaneously quantified by LC-ESI(-)-MS/MS. Following renal IRI only a moderate increase in the kidney levels of IsoP and no relevant change in the trans/cis-epoxy-PUFA ratio was observed. In all investigated cell lines (HCT-116, HepG2 and Caki-2) as well as C. elegans a dose dependent increase of both, IsoP and the trans/cis-epoxy-PUFA ratio in response to the applied t-BOOH was observed. The different cell lines showed a distinct time dependent pattern consistent for both classes of autoxidatively formed oxylipins. Clear and highly significant correlations of the trans/cisepoxy-PUFA ratios with the IsoP levels were found in all investigated cell lines and C. elegans. Based on this, we suggest the trans/cis-epoxy-PUFA ratio as potential new biomarker of oxidative stress, which warrants further investigation.
KW  - Isoprostane
KW  - Trans-epoxy-fatty acid
KW  - Oxidative stress
KW  - Biomarker
KW  - Oxylipin
KW  - Eicosanoid
Y1  - 2019
U6  - https://doi.org/10.1016/j.prostaglandins.2019.04.004
SN  - 1098-8823
SN  - 2212-196X
VL  - 144
PB  - Elsevier
CY  - New York
ER  - 
TY  - JOUR
A1  - Rohn, Isabelle
A1  - Kroepfl, Nina
A1  - Bornhorst, Julia
A1  - Kühnelt, Doris
A1  - Schwerdtle, Tanja
T1  - Side-directed transfer and presystemic metabolism of selenoneine in a human intestinal barrier model
JF  - Molecular nutrition & food research : bioactivity, chemistry, immunology, microbiology, safety, technology
N2  - Scope: Selenoneine, a recently discovered selenium (Se) species mainly present in marine fish, is the Se analogue of ergothioneine, a sulfur-containing purported antioxidant. Although similar properties have been proposed for selenoneine, data on its relevance to human health are yet scarce. Here, the transfer and presystemic metabolism of selenoneine in an in vitro model of the human intestinal barrier are investigated. Methods and results: Selenoneine and the reference species Se-methylselenocysteine (MeSeCys) and selenite are applied to the Caco-2 intestinal barrier model. Selenoneine is transferred in higher amounts, but with similar kinetics as selenite, while MeSeCys shows the highest permeability. In contrast to the reference species, transfer of selenoneine is directed toward the blood side. Cellular Se contents demonstrate that selenoneine is efficiently taken up by Caco-2 cells. Moreover, HPLC/MS-based Se speciation studies reveal a partial metabolism to Se-methylselenoneine, a metabolite previously detected in human blood and urine. Conclusions: Selenoneine is likely to pass the intestinal barrier via transcellular, carrier-mediated transport, is highly bioavailable to Caco-2 cells and undergoes metabolic transformations. Therefore, further studies are needed to elucidate its possible health effects and to characterize the metabolism of selenoneine in humans.
KW  - bioavailability
KW  - Caco-2 intestinal barrier model
KW  - presystemic metabolism
KW  - selenoneine
KW  - Se-methylselenoneine
Y1  - 2019
U6  - https://doi.org/10.1002/mnfr.201900080
SN  - 1613-4125
SN  - 1613-4133
VL  - 63
IS  - 12
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Baesler, Jessica
A1  - Kopp, Johannes Florian
A1  - Pohl, Gabriele
A1  - Aschner, Michael
A1  - Haase, Hajo
A1  - Schwerdtle, Tanja
A1  - Bornhorst, Julia
T1  - Zn homeostasis in genetic models of Parkinson’s disease in Caenorhabditis elegans
JF  - Journal of Trace Elements in Medicine and Biology
N2  - While the underlying mechanisms of Parkinson’s disease (PD) are still insufficiently studied, a complex interaction between genetic and environmental factors is emphasized. Nevertheless, the role of the essential trace element zinc (Zn) in this regard remains controversial. In this study we altered Zn balance within PD models of the versatile model organism Caenorhabditis elegans (C. elegans) in order to examine whether a genetic predisposition in selected genes with relevance for PD affects Zn homeostasis. Protein-bound and labile Zn species act in various areas, such as enzymatic catalysis, protein stabilization pathways and cell signaling. Therefore, total Zn and labile Zn were quantitatively determined in living nematodes as individual biomarkers of Zn uptake and bioavailability with inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) or a multi-well method using the fluorescent probe ZinPyr-1. Young and middle-aged deletion mutants of catp-6 and pdr-1, which are orthologues of mammalian ATP13A2 (PARK9) and parkin (PARK2), showed altered Zn homeostasis following Zn exposure compared to wildtype worms. Furthermore, age-specific differences in Zn uptake were observed in wildtype worms for total as well as labile Zn species. These data emphasize the importance of differentiation between Zn species as meaningful biomarkers of Zn uptake as well as the need for further studies investigating the role of dysregulated Zn homeostasis in the etiology of PD.
KW  - Caenorhabditis elegans
KW  - Zinc
KW  - Zinc homeostasis
KW  - Parkinson disease
KW  - Labile zinc
Y1  - 2019
U6  - https://doi.org/10.1016/j.jtemb.2019.05.005
VL  - 55
SP  - 44
EP  - 49
PB  - Elsevier
CY  - München
ER  - 
TY  - JOUR
A1  - Wardelmann, Kristina
T1  - Hormonal regulation of neuronal mitochondrial unfolded protein response and its impact on metabolism
N2  - The hypothalamus is the main brain area of central regulation of whole body metabolism through impacting food intake and energy expenditure. For the complex regulation, high amounts of energy are needed and mainly provided by mitochondria. Hence, mitochondrial function is crucial for cell homeostasis and modulates central insulin sensitivity. Thus, mitochondrial dysfunction is associated with insulin resistance in the brain and therefore is involved in the pathogenesis of type-2 diabetes (T2D). Mitochondrial health and protein homeostasis is propagated by mitochondrial stress responses like e.g. mitochondrial unfolded protein response (UPRmt). Therefore, studies regarding the regulation of mitochondrial homeostasis are crucial for understanding its effects on the central nervous system (CNS) for the progression of metabolic and nutrition-dependent disorders.
One main aim of this thesis was to investigate the metabolic regulation of mitochondrial stress responsiveness in the hypothalamus. The observed results showed that functional ERK-dependent insulin signaling is needed for regulation of mitochondrial stress response (MSR) genes and positively impacted the metabolism by controlling mitochondrial proteostasis without affecting mitochondrial biogenesis.
To further explore the role of MSR genes for brain cell homeostasis and its consequences for the metabolism, one of the key players - the mitochondrial chaperone heat shock protein 10 (Hsp10) – was studied in detail. Hsp10 expression was decreased in insulin-resistant, hyperglycemic db/db mice brains along with increased protein oxidation. Leptin, another key hormone in regulating metabolism, was able to induce Hsp10 in neurons. Appropriately, lentiviral-mediated knock down (KD) of Hsp10 introduced into hypothalamic CLU-183 cells induced mitochondrial dysfunction, altered mitochondrial dynamics and increased contact sites between mitochondria and endoplasmic reticulum (ER). In addition, Hsp10 KD caused cellular insulin resistance along with increasing oxidative stress specifically in mitochondrial fraction.
Interestingly, acute Hsp10 KD in the arcuate nucleus of the hypothalamus in C57BL/6N male mice did not change body weight or food intake, but it increased plasma leptin concentrations suggesting an effect on global leptin signaling. It increased hepatic markers of gluconeogenesis and hepatic insulin resistance along with features of low-grade inflammation.
Long-term studies of hypothalamic Hsp10 KD mice revealed unaltered systemic insulin sensitivity. The demonstrated increase in markers of hepatic gluconeogenesis of acute Hsp10 KD was still exhibited after 13 weeks, but insulin resistance in the liver was no longer observed.
In conclusion, hypothalamic insulin action regulates MSR and ensures proper mitochondrial function which positively affects metabolism. In addition, hypothalamic Hsp10 acts as a modulator of both insulin and leptin signaling and is identified as pivotal for the regulation of central mitochondrial function as well as insulin sensitivity in the brain and it impacts liver function. It may present a regulator of brain-liver crosstalk influencing hepatic gluconeogenesis and insulin sensitivity through a novel regulatory signaling mechanism.
N2  - Die zentrale Regulation des Metabolismus wird vom Hypothalamus gesteuert, indem diese Hirnregion die Nahrungsaufnahme sowie den Energieverbrauch reguliert. Dieser komplexe Regulations-Mechanismus benötigt eine enorme Menge an Energie, die hauptsächlich von Mitochondrien produziert wird. Somit ist die mitochondriale Funktion existenziell für die Zell-Homöostase und in einigen Studien konnte gezeigt werden, dass diese Funktion ebenfalls mit der zentralen Insulin-Sensitivität zusammenhängt. Mitochondriale Dysfunktion hingegen ist mit Insulin-Resistenz im Gehirn assoziiert und damit an der Pathogenese und Progression von Diabetes Typ 2 beteiligt. Mitochondriale Stressantworten wie zum Beispiel die mitochondriale ungefaltete Proteinantwort (mitochondrial unfolded stress response) ermöglichen die Protein-Homöostase und einwandfreie Funktion der Mitochondrien. Folglich sind Untersuchungen der Regulation der mitochondrialen Funktion von großer Bedeutung für das Verständnis der zentralnervösen Auswirkungen auf die Entwicklung ernährungsbedingter Störungen des Metabolismus.
Eine der Zielstellungen dieser Doktorarbeit war die Untersuchung der metabolischen Regulation der hypothalamische Stressantwort der Mitochondrien. Die hier durchgeführten Studien zeigten, dass die funktionelle Insulin Signalkaskade für die Regulierung der mitochondrialen Stressantwort (MSR) benötigt wird und dies durch die Kontrolle der Proteostase der Mitochondrien positive Effekte auf den Metabolismus hat.
Zur genaueren Klärung der Aufgabe der mitochondrialen Stressantwort für die Homöostase der Gehirnzelle und dessen Auswirkungen für den Metabolismus wurde eines der Mitglieder dieser Stressantwort, das mitochondriale Chaperon Hitzeschock-Protein 10 (Hsp10), näher untersucht. Zunächst konnte dargelegt werden, dass die Expression von Hsp10 in Gehirnen von Insulin-resistenten, hyperglykämischen db/db Mäusen verringert ist. Diese Mäuse zeigen zusätzlich eine Erhöhung der Oxidation von Proteinen im Gehirn, ein weiteres Merkmal des Krankheitsbildes von Diabetes Typ 2. Darüber hinaus zeigten die vorliegenden Studien, dass Leptin, ein weiteres für die Regulation des Metabolismus wichtiges Hormon, die Expression von Hsp10 in Neuronen induzieren konnte. Der lentiviral-vermittelte knockdown von Hsp10 in der hypothalamischen, neuronalen Zelllinie CLU 183 hingegen verursacht mitochondriale Dysfunktion, sowie eine veränderte mitochondriale Dynamik einhergehend mit erhöhtem Kontakt von Mitochondrien mit dem endoplasmatischen Retikulum. Zusätzlich wurde Mitochondrien-spezifischer oxidativer Stress von der Reduzierung von Hsp10 verursacht und eine Insulin-Resistenz ausgelöst.
Interessanterweise beeinflusste der akute knockdown der Hsp10 Expression im Nucleus Arcuatus des Hypothalamus in männlichen C57BL/6N Mäusen weder das Körpergewicht noch die Futteraufnahme, jedoch war die Plasma-Konzentration von Leptin erhöht. Dies deutet auf einen Effekt von zentralem Hsp10 auf die systemische Leptin-Signalwirkung hin. Außerdem wurde durch die akute Verringerung von hypothalamischen Hsp10 PEPCK in der Leber induziert, ein wichtiges Protein der Gluconeogenese, sowie eine hepatische Insulin-Resistenz ausgelöst, verbunden mit Anzeichen einer schwachen Inflammation dieses Gewebes. Bei verlängerter Reduktion der Expression von Hsp10 im Hypothalamus wurde die systemische Insulin-Sensitivität der Mäuse nicht verändert. Die hepatische Insulin-Resistenz war nach 13 Wochen des hypothalamischen knockdown von Hsp10 in C57BL/6N Mäusen nicht mehr zu beobachten, aber die Induktion des Gluconeogenese-Gens PEPCK in der Leber war weiterhin existent.
Zusammenfassend zeigt diese Dissertation, dass die hypothalamische Insulin-Signalwirkung die mitochondriale Stressantwort reguliert und somit die Funktion der Mitochondrien gewährleistet, was den Metabolismus positiv beeinflusst. Des Weiteren deuten die diskutierten Ergebnisse darauf hin, dass Hsp10 im Hypothalamus ein Modulator der Insulin- sowie Leptinsignalwirkung des Körpers ist. Hsp10 ist entscheidend für die Regulierung der zentralen Funktion der Mitochondrien sowie der Insulin-Sensitivität in Gehirn und beeinflusst die Leberfunktion. Die Konsequenzen der Verringerung von Hsp10 im Hypothalamus modulieren die hepatische Gluconeogenese und Insulin-Sensitivität. Daraus folgend wird Hsp10 als neuer Regulator der Kommunikation zwischen Gehirn und Leber identifiziert, mit einem in diesem Falle noch unbekannten Mechanismus der Signalweiterleitung zwischen den beiden Organen.
Y1  - 2019
ER  - 
TY  - JOUR
A1  - Christakoudi, Sofa
A1  - Tsilidis, Konstantinos K.
A1  - Muller, David C.
A1  - Freisling, Heinz
A1  - Weiderpass, Elisabete
A1  - Overvad, Kim
A1  - Söderberg, Stefan
A1  - Häggström, Christel
A1  - Pischon, Tobias
A1  - Dahm, Christina C.
A1  - Zhang, Jie
A1  - Tjønneland, Anne
A1  - Schulze, Matthias Bernd
T1  - A Body Shape Index (ABSI) achieves better mortality risk stratification than alternative indices of abdominal obesity: results from a large European cohort
JF  - Scientific Reports
N2  - Abdominal and general adiposity are independently associated with mortality, but there is no consensus on how best to assess abdominal adiposity. We compared the ability of alternative waist indices to complement body mass index (BMI) when assessing all-cause mortality. We used data from 352,985 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) and Cox proportional hazards models adjusted for other risk factors. During a mean follow-up of 16.1 years, 38,178 participants died. Combining in one model BMI and a strongly correlated waist index altered the association patterns with mortality, to a predominantly negative association for BMI and a stronger positive association for the waist index, while combining BMI with the uncorrelated A Body Shape Index (ABSI) preserved the association patterns. Sex-specific cohort-wide quartiles of waist indices correlated with BMI could not separate high-risk from low-risk individuals within underweight (BMI<18.5 kg/m(2)) or obese (BMI30 kg/m(2)) categories, while the highest quartile of ABSI separated 18-39% of the individuals within each BMI category, which had 22-55% higher risk of death. In conclusion, only a waist index independent of BMI by design, such as ABSI, complements BMI and enables efficient risk stratification, which could facilitate personalisation of screening, treatment and monitoring.
KW  - all-cause mortality
KW  - anthropometric measures
KW  - mass index
KW  - overweight
KW  - cancer
KW  - prediction
KW  - adiposity
KW  - size
Y1  - 2020
VL  - 10
IS  - 1
PB  - Springer Nature
CY  - Berlin
ER  - 
TY  - JOUR
A1  - Castro, Jose Pedro
A1  - Fernando, Raquel
A1  - Reeg, Sandra
A1  - Meinl, Walter
A1  - Almeida, Henrique
A1  - Grune, Tilman
T1  - Non-enzymatic cleavage of Hsp90 by oxidative stress leads to actin aggregate formation
BT  - A novel gain-of-function mechanism
JF  - Redox Biology
N2  - Aging is accompanied by the accumulation of oxidized proteins. To remove them, cells employ the proteasomal and autophagy-lysosomal systems; however, if the clearance rate is inferior to its formation, protein aggregates form as a hallmark of proteostasis loss. In cells, during stress conditions, actin aggregates accumulate leading to impaired proliferation and reduced proteasomal activity, as observed in cellular senescence. The heat shock protein 90 (Hsp90) is a molecular chaperone that binds and protects the proteasome from oxidative inactivation. We hypothesized that in oxidative stress conditions a malfunction of Hsp90 occurs resulting in the aforementioned protein aggregates. Here, we demonstrate that upon oxidative stress Hsp90 loses its function in a highly specific non-enzymatic iron-catalyzed oxidation event and its breakdown product, a cleaved form of Hsp90 (Hsp90cl), acquires a new function in mediating the accumulation of actin aggregates. Moreover, the prevention of Hsp90 cleavage reduces oxidized actin accumulation, whereas transfection of the cleaved form of Hsp90 leads to an enhanced accumulation of oxidized actin. This indicates a clear role of the Hsp90cl in the aggregation of oxidized proteins.
KW  - Oxidative stress
KW  - Protein oxidation
KW  - Heat shock protein 90
KW  - Proteasome
KW  - Protein aggregates
Y1  - 2019
U6  - https://doi.org/10.1016/j.redox.2019.101108
SN  - 2213-2317
VL  - 21
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Raupbach, Jana
A1  - Ott, Christiane
A1  - König, Jeannette
A1  - Grune, Tilman
T1  - Proteasomal degradation of glycated proteins depends on substrate unfolding: Preferred degradation of moderately modified myoglobin
JF  - Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research
N2  - The Maillard reaction generates protein modifications which can accumulate during hyperglycemia or aging and may have inflammatory consequences. The proteasome is one of the major intracellular systems involved in the proteolytic degradation of modified proteins but its role in the degradation of glycated proteins is scarcely studied. In this study, chemical and structural changes of glycated myoglobin were analyzed and its degradation by 20S proteasome was studied. Myoglobin was incubated with physiological (5-10 mM), moderate (50-100 mM) and severe levels (300 mM) of glucose or methylglyoxal (MGO, 50 mM). Glycation increased myoglobin's fluorescence and surface hydrophobicity. Severe glycation generated crosslinked proteins as shown by gel electrophoresis. The concentration of advanced glycation endproducts (AGEs) N-epsilon-carboxymethyl lysine (CML), N-epsilon-carboxyethyl lysine (CEL), methylglyoxal-derived hydroimidazolone-1 (MG-H1), pentosidine and pyrraline was analyzed after enzymatic hydrolysis followed by UPLC-MS/MS. Higher concentrations of glucose increased all analyzed AGEs and incubation with MGO led to a pronounced increase of CEL and MG-H1. The binding of the heme group to apo-myoglobin was decreased with increasing glycation indicating the loss of tertiary protein structure. Proteasomal degradation of modified myoglobin compared to native myoglobin depends on the degree of glycation: physiological conditions decreased proteasomal degradation whereas moderate glycation increased degradation. Severe glycation again decreased proteolytic cleavage which might be due to crosslinking of protein monomers. The activity of the proteasomal subunit beta 5 is influenced by the presence of glycated myoglobin. In conclusion, the role of the proteasome in the degradation of glycated proteins is highly dependent on the level of glycation and consequent protein unfolding.
KW  - Glycation
KW  - Myoglobin
KW  - Heme
KW  - Advanced glycation endproducts
KW  - 20S
KW  - proteasome
Y1  - 2020
U6  - https://doi.org/10.1016/j.freeradbiomed.2019.11.024
SN  - 0891-5849
SN  - 1873-4596
VL  - 152
SP  - 516
EP  - 524
PB  - Elsevier
CY  - New York
ER  - 
TY  - JOUR
A1  - Wiedmer, Petra
A1  - Jung, Tobias
A1  - Castro, Jose Pedro
A1  - Pomatto, Laura C. D.
A1  - Sun, Patrick Y.
A1  - Davies, Kelvin J. A.
A1  - Grune, Tilman
T1  - Sarcopenia
BT  - molecular mechanisms and open questions
JF  - Ageing research reviews : ARR
N2  - Sarcopenia represents a muscle-wasting syndrome characterized by progressive and generalized degenerative loss of skeletal muscle mass, quality, and strength occurring during normal aging. Sarcopenia patients are mainly suffering from the loss in muscle strength and are faced with mobility disorders reducing their quality of life and are, therefore, at higher risk for morbidity (falls, bone fracture, metabolic diseases) and mortality. <br /> Several molecular mechanisms have been described as causes for sarcopenia that refer to very different levels of muscle physiology. These mechanisms cover e. g. function of hormones (e. g. IGF-1 and Insulin), muscle fiber composition and neuromuscular drive, myo-satellite cell potential to differentiate and proliferate, inflammatory pathways as well as intracellular mechanisms in the processes of proteostasis and mitochondrial function. <br /> In this review, we describe sarcopenia as a muscle-wasting syndrome distinct from other atrophic diseases and summarize the current view on molecular causes of sarcopenia development as well as open questions provoking further research efforts for establishing efficient lifestyle and therapeutic interventions.
KW  - molecular pathways
KW  - proteostasis
KW  - proteasome
KW  - autophagy
KW  - mitochondria,
KW  - muscle fibre composition
Y1  - 2020
U6  - https://doi.org/10.1016/j.arr.2020.101200
SN  - 1568-1637
SN  - 1872-9649
VL  - 65
PB  - Elsevier
CY  - Clare
ER  - 
TY  - JOUR
A1  - Schiborn, Catarina
A1  - Schulze, Matthias Bernd
T1  - Precision prognostics for the development of complications in diabetes
JF  - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
N2  - Individuals with diabetes face higher risks for macro- and microvascular complications than their non-diabetic counterparts. The concept of precision medicine in diabetes aims to optimise treatment decisions for individual patients to reduce the risk of major diabetic complications, including cardiovascular outcomes, retinopathy, nephropathy, neuropathy and overall mortality. In this context, prognostic models can be used to estimate an individual's risk for relevant complications based on individual risk profiles. This review aims to place the concept of prediction modelling into the context of precision prognostics. As opposed to identification of diabetes subsets, the development of prediction models, including the selection of predictors based on their longitudinal association with the outcome of interest and their discriminatory ability, allows estimation of an individual's absolute risk of complications. As a consequence, such models provide information about potential patient subgroups and their treatment needs. This review provides insight into the methodological issues specifically related to the development and validation of prediction models for diabetes complications. We summarise existing prediction models for macro- and microvascular complications, commonly included predictors, and examples of available validation studies. The review also discusses the potential of non-classical risk markers and omics-based predictors. Finally, it gives insight into the requirements and challenges related to the clinical applications and implementation of developed predictions models to optimise medical decision making.
KW  - Cardiovascular diseases
KW  - Complications in diabetes
KW  - Macrovascular
KW  - complications
KW  - Microvascular complications
KW  - Personalised medicine
KW  - Precision medicine
KW  - Precision prognostics
KW  - Review
KW  - Risk prediction
KW  - Risk
KW  - scores
Y1  - 2022
U6  - https://doi.org/10.1007/s00125-022-05731-4
SN  - 0012-186X
SN  - 1432-0428
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Wittenbecher, Clemens
A1  - Kuxhaus, Olga
A1  - Boeing, Heiner
A1  - Stefan, Norbert
A1  - Schulze, Matthias Bernd
T1  - Associations of short stature and components of height with incidence of type 2 diabetes
BT  - mediating effects of cardiometabolic risk factors
JF  - Diabetologia : journal of the European Association for the Study of Diabetes (EASD)
N2  - Aims/hypothesis This study aimed to evaluate associations of height as well as components of height (sitting height and leg length) with risk of type 2 diabetes and to explore to what extent associations are explainable by liver fat and cardiometabolic risk markers. Methods A case-cohort study within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study comprising 26,437 participants who provided blood samples was designed. We randomly selected a subcohort of 2500 individuals (2029 diabetes-free at baseline and with anamnestic, anthropometrical and metabolic data for analysis). Of the 820 incident diabetes cases identified in the full cohort during 7 years of follow-up, 698 remained for analyses after similar exclusions. Results After adjustment for age, potential lifestyle confounders, education and waist circumference, greater height was related to lower diabetes risk (HR per 10 cm, men 0.59 [95% CI 0.47, 0.75] and women 0.67 [0.51, 0.88], respectively). Leg length was related to lower risk among men and women, but only among men if adjusted for total height. Adjustment for liver fat and triacylglycerols, adiponectin and C-reactive protein substantially attenuated associations between height and diabetes risk, particularly among women. Conclusions/interpretation We observed inverse associations between height and risk of type 2 diabetes, which was largely related to leg length among men. The inverse associations may be partly driven by lower liver fat content and a more favourable cardiometabolic profile.
KW  - Adult height
KW  - Blood pressure
KW  - Diabetes incidence
KW  - Leg length
KW  - Liver fat
KW  - Short stature
KW  - Trunk length
Y1  - 2019
U6  - https://doi.org/10.1007/s00125-019-04978-8
SN  - 0012-186X
SN  - 1432-0428
VL  - 62
IS  - 12
SP  - 2211
EP  - 2221
PB  - Springer
CY  - New York
ER  - 
TY  - JOUR
A1  - Grune, Tilman
T1  - Oxidized protein aggregates
BT  - formation and biological effects
JF  - Free radical biology and medicine : the official journal of the Oxygen Society, a constituent member of the International Society for Free Radical Research
N2  - The study of protein aggregates has a long history. While in the first decades until the 80ies of the 20th century only the observation of the presence of such aggregates was reported, later the biochemistry of the formation and the biological effects of theses aggregates were described. 
This review focusses on the complexity of the biological effects of protein aggregates and its potential role in the aging process.
Y1  - 2020
U6  - https://doi.org/10.1016/j.freeradbiomed.2020.02.014
SN  - 0891-5849
SN  - 1873-4596
VL  - 150
SP  - 120
EP  - 124
PB  - Elsevier
CY  - New York
ER  - 
TY  - JOUR
A1  - Bishop, Christopher Allen
A1  - Schulze, Matthias Bernd
A1  - Klaus, Susanne
A1  - Weitkunat, Karolin
T1  - The branched-chain amino acids valine and leucine have differential effects on hepatic lipid metabolism
JF  - The FASEB journal : the official journal of the Federation of American Societies for Experimental Biology
N2  - Dairy intake, as a source of branched-chain amino acids (BCAA), has been linked to a lower incidence of type-2-diabetes and increased circulating odd-chain fatty acids (OCFA). To understand this connection, we aimed to investigate differences in BCAA metabolism of leucine and valine, a possible source of OCFA, and their role in hepatic metabolism. Male mice were fed a high-fat diet supplemented with leucine and valine for 1 week and phenotypically characterized with a focus on lipid metabolism. Mouse primary hepatocytes were treated with the BCAA or a Ppar alpha activator WY-14643 to systematically examine direct hepatic effects and their mechanisms. Here, we show that only valine supplementation was able to increase hepatic and circulating OCFA levels via two pathways; a PPAR alpha-dependent induction of alpha-oxidation and an increased supply of propionyl-CoA for de novo lipogenesis. Meanwhile, we were able to confirm leucine-mediated effects on the inhibition of food intake and transport of fatty acids, as well as induction of S6 ribosomal protein phosphorylation. Taken together, these data illustrate differential roles of the BCAA in lipid metabolism and provide preliminary evidence that exclusively valine contributes to the endogenous formation of OCFA which is important for a better understanding of these metabolites in metabolic health.
KW  - fatty acid metabolism
KW  - leucine
KW  - liver
KW  - OCFA
KW  - valine
Y1  - 2020
U6  - https://doi.org/10.1096/fj.202000195R
SN  - 0892-6638
SN  - 1530-6860
VL  - 34
IS  - 7
SP  - 9727
EP  - 9739
PB  - Wiley
CY  - Hoboken
ER  - 
TY  - JOUR
A1  - Schenk, Matthew
A1  - Eichelmann, Fabian
A1  - Schulze, Matthias Bernd
A1  - Rudovich, Natalia
A1  - Pfeiffer, Andreas F. H.
A1  - di Giuseppe, Romina
A1  - Böing, Heiner
A1  - Aleksandrova, Krasimira
T1  - Reproducibility of novel immune-inflammatory biomarkers over 4 months
BT  - an analysis with repeated measures design
JF  - Biomarkers in medicine
N2  - Aim: Assessment of the feasibility and reliability of immune-inflammatory biomarker measurements. Methods: The following biomarkers were assessed in 207 predominantly healthy participants at baseline and after 4 months: MMF, TGF-beta, suPAR and clusterin. Results: Intraclass correlation coefficients (95% CIs) ranged from good for TGF-beta (0.75 [95% CI: 0.33-0.90]) to excellent for MMF (0.81 [95% CI: 0.64-0.90]), clusterin (0.83 [95% CI: 0.78-0.87]) and suPAR (0.91 [95% CI: 0.88-0.93]). Measurement of TGF-beta was challenged by the large number of values below the detection limit. Conclusion: Single measurements of suPAR, clusterin and MMF could serve as feasible and reliable biomarkers of immune-inflammatory pathways in biomedical research.
KW  - clusterin
KW  - immune-inflammatory biomarkers
KW  - MMF
KW  - repeated measures design
KW  - reproducibility
KW  - suPAR
KW  - TGF-beta
Y1  - 2019
U6  - https://doi.org/10.2217/bmm-2018-0351
SN  - 1752-0363
SN  - 1752-0371
VL  - 13
IS  - 8
SP  - 639
EP  - 648
PB  - Future Medicine
CY  - London
ER  - 
TY  - JOUR
A1  - Jannasch, Franziska
A1  - Nickel, Daniela
A1  - Schulze, Matthias Bernd
T1  - The reliability and relative validity of predefined dietary patterns were higher than that of exploratory dietary patterns in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam population
JF  - British journal of nutrition : BJN : an international journal of nutritional science / published on behalf of The Nutrition Society
N2  - The aim of this study was to assess the ability of the FFQ to describe reliable and valid dietary pattern (DP) scores. In a total of 134 participants of the European Prospective Investigation into Cancer and Nutrition-Potsdam study aged 35-67 years, the FFQ was applied twice (baseline and after 1 year) to assess its reliability. Between November 1995 and March 1997, twelve 24-h dietary recalls (24HDR) as reference instrument were applied to assess the validity of the FFQ. Exploratory DP were derived by principal component analyses. Investigated predefined DP were the Alternative Healthy Eating Index (AHEI) and two Mediterranean diet indices. From dietary data of each FFQ, two exploratory DP were retained, but differed in highly loading food groups, resulting in moderate correlations (r 0 center dot 45-0 center dot 58). The predefined indices showed higher correlations between the FFQ (r(AHEI) 0 center dot 62, r(Mediterranean Diet Pyramid Index (MedPyr)) 0 center dot 62 and r(traditional Mediterranean Diet Score (tMDS)) 0 center dot 51). From 24HDR dietary data, one exploratory DP retained differed in composition to the first FFQ-based DP, but showed similarities to the second DP, reflected by a good correlation (r 0 center dot 70). The predefined DP correlated moderately (r 0 center dot 40-0 center dot 60). To conclude, long-term analyses on exploratory DP should be interpreted with caution, due to only moderate reliability. The validity differed extensively for the two exploratory DP. The investigated predefined DP showed a better reliability and a moderate validity, comparable to other studies. Within the two Mediterranean diet indices, the MedPyr performed better than the tMDs in this middle-aged, semi-urban German study population.
KW  - dietary patterns
KW  - reliability
KW  - validity
Y1  - 2020
U6  - https://doi.org/10.1017/S0007114520003517
SN  - 1475-2662
SN  - 0007-1145
VL  - 125
IS  - 11
SP  - 1270
EP  - 1280
PB  - Cambridge University Press
CY  - Cambridge
ER  - 
TY  - JOUR
A1  - Eichelmann, Fabian
A1  - Sellem, Laury
A1  - Wittenbecher, Clemens
A1  - Jäger, Susanne
A1  - Kuxhaus, Olga
A1  - Prada, Marcela
A1  - Cuadrat, Rafael
A1  - Jackson, Kim G.
A1  - Lovegrove, Julie A.
A1  - Schulze, Matthias Bernd
T1  - Deep lipidomics in human plasma: cardiometabolic disease risk and effect of dietary fat modulation
JF  - Circulation
N2  - Background: In blood and tissues, dietary and endogenously generated fatty acids (FAs) occur in free form or as part of complex lipid molecules that collectively represent the lipidome of the respective tissue. We assessed associations of plasma lipids derived from high-resolution lipidomics with incident cardiometabolic diseases and subsequently tested if the identified risk-associated lipids were sensitive to dietary fat modification. Methods: The EPIC Potsdam cohort study (European Prospective Investigation into Cancer and Nutrition) comprises 27 548 participants recruited within an age range of 35 to 65 years from the general population around Potsdam, Germany. We generated 2 disease-specific case cohorts on the basis of a fixed random subsample (n=1262) and all respective cohort-wide identified incident primary cardiovascular disease (composite of fatal and nonfatal myocardial infarction and stroke; n=551) and type 2 diabetes (n=775) cases. We estimated the associations of baseline plasma concentrations of 282 class-specific FA abundances (calculated from 940 distinct molecular species across 15 lipid classes) with the outcomes in multivariable-adjusted Cox models. We tested the effect of an isoenergetic dietary fat modification on risk-associated lipids in the DIVAS randomized controlled trial (Dietary Intervention and Vascular Function; n=113). Participants consumed either a diet rich in saturated FAs (control), monounsaturated FAs, or a mixture of monounsaturated and n-6 polyunsaturated FAs for 16 weeks. Results: Sixty-nine lipids associated (false discovery rate<0.05) with at least 1 outcome (both, 8; only cardiovascular disease, 49; only type 2 diabetes, 12). In brief, several monoacylglycerols and FA16:0 and FA18:0 in diacylglycerols were associated with both outcomes; cholesteryl esters, free fatty acids, and sphingolipids were largely cardiovascular disease specific; and several (glycero)phospholipids were type 2 diabetes specific. In addition, 19 risk-associated lipids were affected (false discovery rate<0.05) by the diets rich in unsaturated dietary FAs compared with the saturated fat diet (17 in a direction consistent with a potential beneficial effect on long-term cardiometabolic risk). For example, the monounsaturated FA-rich diet decreased diacylglycerol(FA16:0) by 0.4 (95% CI, 0.5-0.3) SD units and increased triacylglycerol(FA22:1) by 0.5 (95% CI, 0.4-0.7) SD units. Conclusions: We identified several lipids associated with cardiometabolic disease risk. A subset was beneficially altered by a dietary fat intervention that supports the substitution of dietary saturated FAs with unsaturated FAs as a potential tool for primary disease prevention.
KW  - cardiovascular diseases
KW  - cholesterol
KW  - diabetes mellitus
KW  - type 2
KW  - diet
KW  - food
KW  - and nutrition
KW  - epidemiology
KW  - lipids
Y1  - 2022
U6  - https://doi.org/10.1161/CIRCULATIONAHA.121.056805
SN  - 0009-7322
SN  - 1524-4539
VL  - 146
IS  - 1
SP  - 21
EP  - 35
PB  - Lippincott Williams & Wilkins
CY  - Philadelphia
ER  - 
TY  - JOUR
A1  - Schröter, David
A1  - Neugart, Susanne
A1  - Schreiner, Monika
A1  - Grune, Tilman
A1  - Rohn, Sascha
A1  - Ott, Christiane
T1  - Amaranth’s 2-Caffeoylisocitric Acid—An Anti-Inflammatory Caffeic Acid Derivative That Impairs NF-κB Signaling in LPS-Challenged RAW 264.7 Macrophages
JF  - Nutrients
N2  - For centuries, Amaranthus sp. were used as food, ornamentals, and medication. Molecular mechanisms, explaining the health beneficial properties of amaranth, are not yet understood, but have been attributed to secondary metabolites, such as phenolic compounds. One of the most abundant phenolic compounds in amaranth leaves is 2-caffeoylisocitric acid (C-IA) and regarding food occurrence, C-IA is exclusively found in various amaranth species. In the present study, the anti-inflammatory activity of C-IA, chlorogenic acid, and caffeic acid in LPS-challenged macrophages (RAW 264.7) has been investigated and cellular contents of the caffeic acid derivatives (CADs) were quantified in the cells and media. The CADs were quantified in the cell lysates in nanomolar concentrations, indicating a cellular uptake. Treatment of LPS-challenged RAW 264.7 cells with 10 µM of CADs counteracted the LPS effects and led to significantly lower mRNA and protein levels of inducible nitric oxide synthase, tumor necrosis factor alpha, and interleukin 6, by directly decreasing the translocation of the nuclear factor κB/Rel-like containing protein 65 into the nucleus. This work provides new insights into the molecular mechanisms that attribute to amaranth’s anti-inflammatory properties and highlights C-IA’s potential as a health-beneficial compound for future research.
KW  - inflammation
KW  - caffeic acid derivatives
KW  - RAW 264
KW  - 7 macrophages
KW  - NF-kappa B
KW  - amaranth
Y1  - 2019
U6  - https://doi.org/10.3390/nu11030571
SN  - 2072-6643
VL  - 11
IS  - 3
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Eichelmann, Fabian
A1  - Schulze, Matthias Bernd
A1  - Wittenbecher, Clemens
A1  - Menzel, Juliane
A1  - Weikert, Cornelia
A1  - di Giuseppe, Romina
A1  - Biemann, Ronald
A1  - Isermann, Berend
A1  - Fritsche, Andreas
A1  - Boeing, Heiner
A1  - Aleksandrova, Krasimira
T1  - Association of Chemerin Plasma Concentration With Risk of Colorectal Cancer
JF  - JAMA network open
N2  - IMPORTANCE Inflammatory processes have been suggested to have an important role in colorectal cancer (CRC) etiology. Chemerin is a recently discovered inflammatory biomarker thought to exert chemotactic, adipogenic, and angiogenic functions. However, its potential link with CRC has not been sufficiently explored. OBJECTIVE To evaluate the prospective association of circulating plasma chemerin concentrations with incident CRC. DESIGN, SETTING, AND PARTICIPANTS Prospective case-cohort study based on 27 548 initially healthy participants from the European Prospective Investigation Into Cancer and Nutrition (EPIC)-Potsdam cohort who were followed for up to 16 years. Baseline study information and samples were collected between August 23, 1994, and September 25, 1998. Recruitment was according to random registry sampling from the geographical area of Potsdam, Germany, and surrounding municipalities. The last date of study follow-up was May 10, 2010. Statistical analysis was conducted in 2018. MAIN OUTCOMES AND MEASURES Incident CRC, colon cancer, and rectal cancer. Baseline chemerin plasma concentrations were measured by enzyme-linked immunosorbent assay. CONCLUSIONS AND RELEVANCE This study found that the association between chemerin concentration and the risk of incident CRC was linear and independent of established CRC risk factors. Further studies are warranted to evaluate chemerin as a novel immune-inflammatory agent in colorectal carcinogenesis.
Y1  - 2019
U6  - https://doi.org/10.1001/jamanetworkopen.2019.0896
SN  - 2574-3805
VL  - 2
IS  - 3
PB  - American Veterinary Medical Association
CY  - Chicago
ER  - 
TY  - JOUR
A1  - Johann, Kornelia
A1  - Kleinert, Maximilian
A1  - Klaus, Susanne
T1  - The role of GDF15 as a myomitokine
JF  - Cells
N2  - Growth differentiation factor 15 (GDF15) is a cytokine best known for affecting systemic energy metabolism through its anorectic action. GDF15 expression and secretion from various organs and tissues is induced in different physiological and pathophysiological states, often linked to mitochondrial stress, leading to highly variable circulating GDF15 levels. 

In skeletal muscle and the heart, the basal expression of GDF15 is very low compared to other organs, but GDF15 expression and secretion can be induced in various stress conditions, such as intense exercise and acute myocardial infarction, respectively. GDF15 is thus considered as a myokine and cardiokine. GFRAL, the exclusive receptor for GDF15, is expressed in hindbrain neurons and activation of the GDF15-GFRAL pathway is linked to an increased sympathetic outflow and possibly an activation of the hypothalamic-pituitary-adrenal (HPA) stress axis. 

There is also evidence for peripheral, direct effects of GDF15 on adipose tissue lipolysis and possible autocrine cardiac effects. Metabolic and behavioral outcomes of GDF15 signaling can be beneficial or detrimental, likely depending on the magnitude and duration of the GDF15 signal. 
This is especially apparent for GDF15 production in muscle, which can be induced both by exercise and by muscle disease states such as sarcopenia and mitochondrial myopathy.
KW  - anorexia
KW  - appetite regulation
KW  - cardiokine
KW  - cytokine
KW  - exercise
KW  - mitochondria
KW  - muscle
KW  - myokine
KW  - myopathy
KW  - sarcopenia
Y1  - 2021
U6  - https://doi.org/10.3390/cells10112990
SN  - 2073-4409
VL  - 10
IS  - 11
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Kessler, Katharina
A1  - Hornemann, Silke
A1  - Rudovich, Natalia
A1  - Weber, Daniela
A1  - Grune, Tilman
A1  - Kramer, Achim
A1  - Pfeiffer, Andreas F. H.
A1  - Pivovarova-Ramich, Olga
T1  - Saliva samples as a tool to study the effect of meal timing on metabolic and inflammatory biomarkers
JF  - Nutrients
N2  - Meal timing affects metabolic regulation in humans. Most studies use blood samples fortheir investigations. Saliva, although easily available and non-invasive, seems to be rarely used forchrononutritional studies. In this pilot study, we tested if saliva samples could be used to studythe effect of timing of carbohydrate and fat intake on metabolic rhythms. In this cross-over trial, 29 nonobese men were randomized to two isocaloric 4-week diets: (1) carbohydrate-rich meals until13:30 and high-fat meals between 16:30 and 22:00 or (2) the inverse order of meals. Stimulated salivasamples were collected every 4 h for 24 h at the end of each intervention, and levels of hormones andinflammatory biomarkers were assessed in saliva and blood. Cortisol, melatonin, resistin, adiponectin, interleukin-6 and MCP-1 demonstrated distinct diurnal variations, mirroring daytime reports inblood and showing significant correlations with blood levels. The rhythm patterns were similar forboth diets, indicating that timing of carbohydrate and fat intake has a minimal effect on metabolicand inflammatory biomarkers in saliva. Our study revealed that saliva is a promising tool for thenon-invasive assessment of metabolic rhythms in chrononutritional studies, but standardisation of sample collection is needed in out-of-lab studies.
KW  - meal timing
KW  - saliva
KW  - circadian clock
KW  - adiponectin
KW  - resistin
KW  - visfatin
KW  - insulin
KW  - melatonin
KW  - cortisol
KW  - cytokines
Y1  - 2020
U6  - https://doi.org/10.3390/nu12020340
SN  - 2072-6643
IS  - 2
SP  - 1
EP  - 12
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Klopsch, Rebecca
A1  - Baldermann, Susanne
A1  - Hanschen, Franziska S.
A1  - Voss, Alexander
A1  - Rohn, Sascha
A1  - Schreiner, Monika
A1  - Neugart, Susanne
T1  - Brassica-enriched wheat bread: Unraveling the impact of ontogeny and breadmaking on bioactive secondary plant metabolites of pak choi and kale
JF  - Food chemistry
N2  - Consumption of Brassica vegetables is linked to health benefits, as they contain high concentrations of the following secondary plant metabolites (SPMs): glucosinolate breakdown products, carotenoids, chlorophylls, and phenolic compounds. Especially Brassica vegetables are consumed as microgreens (developed cotyledons). It was investigated how different ontogenetic stages (microgreens or leaves) of pak choi (Brassica rapa subsp. chinensis) and kale (Brassica oleracea var. sabellica) differ in their SPM concentration. The impact of breadmaking on SPMs in microgreens (7 days) and leaves (14 days) in pak choi and kale as a supplement in mixed wheat bread was assessed. In leaves, carotenoids, chlorophylls, and phenolic compounds were higher compared to those of microgreens. Breadmaking caused a decrease of SPMs. Chlorophyll degradation was observed, leading to pheophytin and pyropheophytin formation. In kale, sinapoylgentiobiose, a hydroxycinnamic acid derivative, concentration increased. Thus, leaves of Brassica species are suitable as natural ingredients for enhancing bioactive SPM concentrations in bread.
KW  - Ontogeny
KW  - Brassica
KW  - Glucosinolate breakdown product
KW  - Flavonoid
KW  - Carotenoid
KW  - Thermal processing
Y1  - 2019
U6  - https://doi.org/10.1016/j.foodchem.2019.05.113
SN  - 0308-8146
SN  - 1873-7072
VL  - 295
SP  - 412
EP  - 422
PB  - Elsevier
CY  - Oxford
ER  - 
TY  - JOUR
A1  - Cramer, Sandra
A1  - Tacke, Sebastian
A1  - Bornhorst, Julia
A1  - Klingauf, Jürgen
A1  - Schwerdtle, Tanja
A1  - Galla, Hans-Joachim
T1  - The Influence of Silver Nanoparticles on the Blood-Brain and the Blood-Cerebrospinal Fluid Barrier in vitro
JF  - Journal of Nanomedicine & Nanotechnology
N2  - The use of silver nanoparticles in medical and consumer products such as wound dressings, clothing and cosmetic has increased significantly in recent years. Still, the influence of these particles on our health and especially on our brain, has not been examined adequately up to now. We studied the influence of AgEO- (Ethylene Oxide) and AgCitrate-Nanoparticles (NPs) on the protective barriers of the brain, namely the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (blood-CSF) barrier in vitro. The NPs toxicity was evaluated by examining changes in membrane integrity, cell morphology, barrier properties, oxidative stress and inflammatory reactions. AgNPs decreased cell viability, disturbed barrier integrity and tight junctions and triggered oxidative stress and DNA strand breaks. However, all mentioned effects were, at least partly, suppressed by a Citrate-coating and were most pronounced in the cells of the BBB as compared to the epithelial cells representing the blood-CSF barrier. AgEO- but not AgCitrate-NPs also triggered an inflammatory reaction in porcine brain capillary endothelial cells (PBCEC), which represent the BBB.
Our data indicate that AgNPs may cause adverse effects within the barriers of the brain, but their toxicity can be reduced by choosing an appropriate coating material.
Y1  - 2014
U6  - https://doi.org/10.4172/2157-7439.1000225
SN  - 2157-7439
VL  - 5
IS  - 5
ER  - 
TY  - JOUR
A1  - Figueroa Campos, Gustavo Adolfo
A1  - Perez, Jeffrey Paulo H.
A1  - Block, Inga
A1  - Sagu Tchewonpi, Sorel
A1  - Saravia Celis, Pedro
A1  - Taubert, Andreas
A1  - Rawel, Harshadrai Manilal
T1  - Preparation of activated carbons from spent coffee and coffee parchment and assessment of their adsorbent efficiency
JF  - Processes : open access journal
N2  - The valorization of coffee wastes through modification to activated carbon has been considered as a low-cost adsorbent with prospective to compete with commercial carbons. So far, very few studies have referred to the valorization of coffee parchment into activated carbon. Moreover, low-cost and efficient activation methods need to be more investigated. The aim of this work was to prepare activated carbon from spent coffee grounds and parchment, and to assess their adsorption performance. The co-calcination processing with calcium carbonate was used to prepare the activated carbons, and their adsorption capacity for organic acids, phenolic compounds and proteins was evaluated. Both spent coffee grounds and parchment showed yields after the calcination and washing treatments of around 9.0%. The adsorption of lactic acid was found to be optimal at pH 2. The maximum adsorption capacity of lactic acid with standard commercial granular activated carbon was 73.78 mg/g, while the values of 32.33 and 14.73 mg/g were registered for the parchment and spent coffee grounds activated carbons, respectively. The Langmuir isotherm showed that lactic acid was adsorbed as a monolayer and distributed homogeneously on the surface. Around 50% of total phenols and protein content from coffee wastewater were adsorbed after treatment with the prepared activated carbons, while 44, 43, and up to 84% of hydrophobic compounds were removed using parchment, spent coffee grounds and commercial activated carbon, respectively; the adsorption efficiencies of hydrophilic compounds ranged between 13 and 48%. Finally, these results illustrate the potential valorization of coffee by-products parchment and spent coffee grounds into activated carbon and their use as low-cost adsorbent for the removal of organic compounds from aqueous solutions.
KW  - coffee by-products
KW  - spent coffee grounds
KW  - parchment
KW  - valorization
KW  - calcination
KW  - activated carbon
KW  - organic compounds adsorption
Y1  - 2021
U6  - https://doi.org/10.3390/pr9081396
SN  - 2227-9717
VL  - 9
IS  - 8
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Weber, Daniela
A1  - Kochlik, Bastian Max
A1  - Demuth, Ilja
A1  - Steinhagen-Thiessen, Elisabeth
A1  - Grune, Tilman
A1  - Norman, Kristina
T1  - Plasma carotenoids, tocopherols and retinol
BT  - Association with age in the Berlin Aging Study II
JF  - Redox Biology
N2  - Regular consumption of fruits and vegetables, which is related to high plasma levels of lipid-soluble micro-nutrients such as carotenoids and tocopherols, is linked to lower incidences of various age-related diseases. Differences in lipid-soluble micronutrient blood concentrations seem to be associated with age. Our retrospective analysis included men and women aged 22-37 and 60-85 years from the Berlin Aging Study II. Participants with simultaneously available plasma samples and dietary data were included (n = 1973). Differences between young and old groups were found for plasma lycopene, alpha-carotene, alpha-tocopherol, beta-cryptoxanthin (only in women), and gamma-tocopherol (only in men). beta-Carotene, retinol and lutein/zeaxanthin did not differ between young and old participants regardless of the sex. We found significant associations for lycopene, alpha-carotene (both inverse), alpha-tocopherol, gamma-tocopherol, and beta-carotene (all positive) with age. Adjusting for BMI, smoking status, season, cholesterol and dietary intake confirmed these associations, except for beta-carotene. These micronutrients are important antioxidants and associated with lower incidence of age-related diseases, therefore it is important to understand the underlying mechanisms in order to implement dietary strategies for the prevention of age-related diseases. To explain the lower lycopene and alpha-carotene concentration in older subjects, bioavailability studies in older participants are necessary.
KW  - carotenoids
KW  - tocopherols
KW  - micronutrients
KW  - age
KW  - plasma
KW  - food frequency questionnaire
Y1  - 2020
U6  - https://doi.org/10.1016/j.redox.2020.101461
SN  - 2213-2317
VL  - 32
SP  - 1
EP  - 8
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Schell, Mareike
A1  - Wardelmann, Kristina
A1  - Hauffe, Robert
A1  - Rath, Michaela
A1  - Chopra, Simran
A1  - Kleinridders, André
T1  - Lactobacillus rhamnosus sex-specifically attenuates depressive-like behavior and mitigates metabolic consequences in obesity
JF  - Biological psychiatry: global open science
N2  - BACKGROUND: Patients with diabetes exhibit an increased prevalence for emotional disorders compared with healthy humans, partially due to a shared pathogenesis including hormone resistance and inflammation, which is also linked to intestinal dysbiosis. The preventive intake of probiotic lactobacilli has been shown to improve dysbiosis along with mood and metabolism. Yet, a potential role of Lactobacillus rhamnosus (Lacticaseibacillus rhamnosus 0030) (LR) in improving emotional behavior in established obesity and the underlying mechanisms are unknown.

METHODS: Female and male C57BL/6N mice were fed a low-fat diet (10% kcal from fat) or high-fat diet (HFD) (45% kcal from fat) for 6 weeks, followed by daily oral gavage of vehicle or 1 3 10 8 colony-forming units of LR, and assessment of anxiety- and depressive-like behavior. Cecal microbiota composition was analyzed using 16S ribosomal RNA sequencing, plasma and cerebrospinal fluid were collected for metabolomic analysis, and gene expression of different brain areas was assessed using reverse transcriptase quantitative polymerase chain reaction.

RESULTS: We observed that 12 weeks of HFD feeding induced hyperinsulinemia, which was attenuated by LR application only in female mice. On the contrary, HFD-fed male mice exhibited increased anxiety- and depressive-like behavior, where the latter was specifically attenuated by LR application, which was independent of metabolic changes. Furthermore, LR application restored the HFD-induced decrease of tyrosine hydroxylase, along with normalizing cholecystokinin gene expression in dopaminergic brain regions; both tyrosine hydroxylase and cholecystokinin are involved in signaling pathways impacting emotional disorders.

CONCLUSIONS: Our data show that LR attenuates depressive-like behavior after established obesity, with changes in the dopaminergic system in male mice, and mitigates hyperinsulinemia in obese female mice.
Y1  - 2023
U6  - https://doi.org/10.1016/j.bpsgos.2023.02.011
SN  - 2667-1743
VL  - 3
IS  - 4
SP  - 651
EP  - 662
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Müller, Sandra Marie
A1  - Ebert, Franziska
A1  - Raber, Georg
A1  - Meyer, Sören
A1  - Bornhorst, Julia
A1  - Hüwel, Stephan
A1  - Galla, Hans-Joachim
A1  - Francesconi, Kevin A.
A1  - Schwerdtle, Tanja
T1  - Effects of arsenolipids on in vitro blood-brain barrier model
JF  - Archives of toxicology : official journal of EUROTOX
N2  - Arsenic-containing hydrocarbons (AsHCs), a subgroup of arsenolipids (AsLs) occurring in fish and edible algae, possess a substantial neurotoxic potential in fully differentiated human brain cells. Previous in vivo studies indicating that AsHCs cross the blood–brain barrier of the fruit fly Drosophila melanogaster raised the question whether AsLs could also cross the vertebrate blood–brain barrier (BBB). In the present study, we investigated the impact of several representatives of AsLs (AsHC 332, AsHC 360, AsHC 444, and two arsenic-containing fatty acids, AsFA 362 and AsFA 388) as well as of their metabolites (thio/oxo-dimethylpropionic acid, dimethylarsinic acid) on porcine brain capillary endothelial cells (PBCECs, in vitro model for the blood–brain barrier). AsHCs exerted the strongest cytotoxic effects of all investigated arsenicals as they were up to fivefold more potent than the toxic reference species arsenite (iAsIII). In our in vitro BBB-model, we observed a slight transfer of AsHC 332 across the BBB after 6 h at concentrations that do not affect the barrier integrity. Furthermore, incubation with AsHCs for 72 h led to a disruption of the barrier at sub-cytotoxic concentrations. The subsequent immunocytochemical staining of three tight junction proteins revealed a significant impact on the cell membrane. Because AsHCs enhance the permeability of the in vitro blood–brain barrier, a similar behavior in an in vivo system cannot be excluded. Consequently, AsHCs might facilitate the transfer of accompanying foodborne toxicants into the brain.
KW  - Arsenolipids
KW  - Arsenic-containing hydrocarbons
KW  - Arsenic-containing fatty acids
KW  - In vitro blood-brain barrier model
Y1  - 2017
SN  - 0340-5761
SN  - 1432-0738
VL  - 92
IS  - 2
SP  - 823
EP  - 832
PB  - Springer
CY  - Heidelberg
ER  - 
TY  - JOUR
A1  - Rothwell, Joseph A.
A1  - Murphy, Neil
A1  - Aleksandrova, Krasimira
A1  - Schulze, Matthias Bernd
A1  - Bešević, Jelena
A1  - Kliemann, Nathalie
A1  - Jenab, Mazda
A1  - Ferrari, Pietro
A1  - Achaintre, David
A1  - Gicquiau, Audrey
A1  - Vozar, Béatrice
A1  - Scalbert, Augustin
A1  - Huybrechts, Inge
A1  - Freisling, Heinz
A1  - Prehn, Cornelia
A1  - Adamski, Jerzy
A1  - Cross, Amanda J.
A1  - Pala, Valeria Maria
A1  - Boutron-Ruault, Marie-Christine
A1  - Dahm, Christina C.
A1  - Overvad, Kim
A1  - Gram, Inger Torhild
A1  - Sandanger, Torkjel M.
A1  - Skeie, Guri
A1  - Jakszyn, Paula
A1  - Tsilidis, Kostas K.
A1  - Hughes, David J.
A1  - van Guelpen, Bethany
A1  - Bodén, Stina
A1  - Sánchez, Maria-José
A1  - Schmidt, Julie A.
A1  - Katzke, Verena
A1  - Kühn, Tilman
A1  - Colorado-Yohar, Sandra
A1  - Tumino, Rosario
A1  - Bueno-de-Mesquita, Bas
A1  - Vineis, Paolo
A1  - Masala, Giovanna
A1  - Panico, Salvatore
A1  - Eriksen, Anne Kirstine
A1  - Tjønneland, Anne
A1  - Aune, Dagfinn
A1  - Weiderpass, Elisabete
A1  - Severi, Gianluca
A1  - Chajès, Véronique
A1  - Gunter, Marc J.
T1  - Metabolic signatures of healthy lifestyle patterns and colorectal cancer risk in a European cohort
JF  - Clinical gastroenterology and hepatology
N2  - BACKGROUND & AIMS: Colorectal cancer risk can be lowered by adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines. We derived metabolic signatures of adherence to these guidelines and tested their associations with colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort.

METHODS: Scores reflecting adherence to the WCRF/AICR recommendations (scale, 1-5) were calculated from participant data on weight maintenance, physical activity, diet, and alcohol among a discovery set of 5738 cancer-free European Prospective Investigation into Cancer and Nutrition participants with metabolomics data. Partial least-squares regression was used to derive fatty acid and endogenous metabolite signatures of the WCRF/AICR score in this group. In an independent set of 1608 colorectal cancer cases and matched controls, odds ratios (ORs) and 95% CIs were calculated for colorectal cancer risk per unit increase in WCRF/AICR score and per the corresponding change in metabolic signatures using multivariable conditional logistic regression.

RESULTS: Higher WCRF/AICR scores were characterized by metabolic signatures of increased odd-chain fatty acids, serine, glycine, and specific phosphatidylcholines. Signatures were inversely associated more strongly with colorectal cancer risk (fatty acids: OR, 0.51 per unit increase; 95% CI, 0.29-0.90; endogenous metabolites: OR, 0.62 per unit change; 95% CI, 0.50-0.78) than the WCRF/AICR score (OR, 0.93 per unit change; 95% CI, 0.86-1.00) overall. Signature associations were stronger in male compared with female participants.

CONCLUSIONS: Metabolite profiles reflecting adherence to WCRF/AICR guidelines and additional lifestyle or biological risk factors were associated with colorectal cancer. Measuring a specific panel of metabolites representative of a healthy or unhealthy lifestyle may identify strata of the population at higher risk of colorectal cancer.
KW  - colorectal neoplasm
KW  - risk factors
KW  - World Cancer Research Fund/American Institute for Cancer Research Recommendations
KW  - targeted metabolomics
Y1  - 2020
U6  - https://doi.org/10.1016/j.cgh.2020.11.045
SN  - 1542-3565
SN  - 1542-7714
VL  - 20
SP  - E1061
EP  - E1082
PB  - Elsevier
CY  - New York, NY
ER  - 
TY  - JOUR
A1  - Harms, Laura M.
A1  - Scalbert, Augustin
A1  - Zamora-Ros, Raul
A1  - Rinaldi, Sabina
A1  - Jenab, Mazda
A1  - Murphy, Neil
A1  - Achaintre, David
A1  - Tjønneland, Anne
A1  - Olsen, Anja
A1  - Overvad, Kim
A1  - Aleksandrova, Krasimira
T1  - Plasma polyphenols associated with lower high-sensitivity C-reactive protein concentrations
BT  - a cross-sectional study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort
JF  - British Journal of Nutrition
N2  - Experimental studies have reported on the anti-inflammatory properties of polyphenols. However, results from epidemiological investigations have been inconsistent and especially studies using biomarkers for assessment of polyphenol intake have been scant. We aimed to characterise the association between plasma concentrations of thirty-five polyphenol compounds and low-grade systemic inflammation state as measured by high-sensitivity C-reactive protein (hsCRP). A cross-sectional data analysis was performed based on 315 participants in the European Prospective Investigation into Cancer and Nutrition cohort with available measurements of plasma polyphenols and hsCRP. In logistic regression analysis, the OR and 95 % CI of elevated serum hsCRP (>3 mg/l) were calculated within quartiles and per standard deviation higher level of plasma polyphenol concentrations. In a multivariable-adjusted model, the sum of plasma concentrations of all polyphenols measured (per standard deviation) was associated with 29 (95 % CI 50, 1) % lower odds of elevated hsCRP. In the class of flavonoids, daidzein was inversely associated with elevated hsCRP (OR 0 center dot 66, 95 % CI 0 center dot 46, 0 center dot 96). Among phenolic acids, statistically significant associations were observed for 3,5-dihydroxyphenylpropionic acid (OR 0 center dot 58, 95 % CI 0 center dot 39, 0 center dot 86), 3,4-dihydroxyphenylpropionic acid (OR 0 center dot 63, 95 % CI 0 center dot 46, 0 center dot 87), ferulic acid (OR 0 center dot 65, 95 % CI 0 center dot 44, 0 center dot 96) and caffeic acid (OR 0 center dot 69, 95 % CI 0 center dot 51, 0 center dot 93). The odds of elevated hsCRP were significantly reduced for hydroxytyrosol (OR 0 center dot 67, 95 % CI 0 center dot 48, 0 center dot 93). The present study showed that polyphenol biomarkers are associated with lower odds of elevated hsCRP. Whether diet rich in bioactive polyphenol compounds could be an effective strategy to prevent or modulate deleterious health effects of inflammation should be addressed by further well-powered longitudinal studies.
KW  - polyphenols
KW  - plasma measurements
KW  - C-reactive protein
KW  - inflammation
KW  - chronic diseases
Y1  - 2019
U6  - https://doi.org/10.1017/S0007114519002538
SN  - 0007-1145
SN  - 1475-2662
VL  - 123
IS  - 2
SP  - 198
EP  - 208
PB  - Cambridge University Press
CY  - Cambridge
ER  - 
TY  - JOUR
A1  - Winkelbeiner, Nicola Lisa
A1  - Wandt, Viktoria Klara Veronika
A1  - Ebert, Franziska
A1  - Lossow, Kristina
A1  - Bankoglu, Ezgi E.
A1  - Martin, Maximilian
A1  - Mangerich, Aswin
A1  - Stopper, Helga
A1  - Bornhorst, Julia
A1  - Kipp, Anna Patricia
A1  - Schwerdtle, Tanja
T1  - A Multi-Endpoint Approach to Base Excision Repair Incision Activity Augmented by PARylation and DNA Damage Levels in Mice
BT  - Impact of Sex and Age
JF  - International Journal of Molecular Sciences
N2  - Investigation of processes that contribute to the maintenance of genomic stability is one crucial factor in the attempt to understand mechanisms that facilitate ageing. The DNA damage response (DDR) and DNA repair mechanisms are crucial to safeguard the integrity of DNA and to prevent accumulation of persistent DNA damage. Among them, base excision repair (BER) plays a decisive role. BER is the major repair pathway for small oxidative base modifications and apurinic/apyrimidinic (AP) sites. We established a highly sensitive non-radioactive assay to measure BER incision activity in murine liver samples. Incision activity can be assessed towards the three DNA lesions 8-oxo-2’-deoxyguanosine (8-oxodG), 5-hydroxy-2’-deoxyuracil (5-OHdU), and an AP site analogue. We applied the established assay to murine livers of adult and old mice of both sexes. Furthermore, poly(ADP-ribosyl)ation (PARylation) was assessed, which is an important determinant in DDR and BER. Additionally, DNA damage levels were measured to examine the overall damage levels. No impact of ageing on the investigated endpoints in liver tissue were found. However, animal sex seems to be a significant impact factor, as evident by sex-dependent alterations in all endpoints investigated. Moreover, our results revealed interrelationships between the investigated endpoints indicative for the synergetic mode of action of the cellular DNA integrity maintaining machinery.
KW  - maintenance of genomic integrity
KW  - ageing
KW  - sex
KW  - DNA damage
KW  - base excision repair (incision activity)
KW  - DNA damage response
KW  - poly(ADP-ribosyl)ation
KW  - liver
Y1  - 2020
U6  - https://doi.org/10.3390/ijms21186600
SN  - 1422-0067
VL  - 21
IS  - 18
PB  - Molecular Diversity Preservation International
CY  - Basel
ER  - 
TY  - JOUR
A1  - Gisch, Ulrike Alexandra
A1  - Robert, Margaux
A1  - Berlin, Noemi
A1  - Nebout, Antoine
A1  - Etile, Fabrice
A1  - Teyssier, Sabrina
A1  - Andreeva, Valentina A.
A1  - Hercberg, Serge
A1  - Touvier, Mathilde
A1  - Peneau, Sandrine
T1  - Mastery is associated with weight status, food intake, snacking, and eating disorder symptoms in the NutriNet-Sante cohort study
JF  - Frontiers in Nutrition
N2  - Mastery is a psychological resource that is defined as the extent to which individuals perceive having control over important circumstances of their lives. Although mastery has been associated with various physical and psychological health outcomes, studies assessing its relationship with weight status and dietary behavior are lacking. The aim of this cross-sectional study was to assess the relationship between mastery and weight status, food intake, snacking, and eating disorder (ED) symptoms in the NutriNet-Sante cohort study. Mastery was measured with the Pearlin Mastery Scale (PMS) in 32,588 adults (77.45% female), the mean age was 50.04 (14.53) years. Height and weight were self-reported. Overall diet quality and food group consumption were evaluated with >= 3 self-reported 24-h dietary records (range: 3-27). Snacking was assessed with an ad-hoc question. ED symptoms were assessed with the Sick-Control-One-Fat-Food Questionnaire (SCOFF). Linear and logistic regression analyses were conducted to assess the relationship between mastery and weight status, food intake, snacking, and ED symptoms, controlling for sociodemographic and lifestyle characteristics. Females with a higher level of mastery were less likely to be underweight (OR: 0.88; 95%CI: 0.84, 0.93), overweight [OR: 0.94 (0.91, 0.97)], or obese [class I: OR: 0.86 (0.82, 0.90); class II: OR: 0.76 (0.71, 0.82); class III: OR: 0.77 (0.69, 0.86)]. Males with a higher level of mastery were less likely to be obese [class III: OR: 0.75 (0.57, 0.99)]. Mastery was associated with better diet quality overall, a higher consumption of fruit and vegetables, seafood, wholegrain foods, legumes, non-salted oleaginous fruits, and alcoholic beverages and with a lower consumption of meat and poultry, dairy products, sugary and fatty products, milk-based desserts, and sweetened beverages. Mastery was also associated with lower snacking frequency [OR: 0.89 (0.86, 0.91)] and less ED symptoms [OR: 0.73 (0.71, 0.75)]. As mastery was associated with favorable dietary behavior and weight status, targeting mastery might be a promising approach in promoting healthy behaviors.
KW  - mastery
KW  - locus of control
KW  - weight status
KW  - diet quality
KW  - food group consumption
KW  - snacking
KW  - eating disorder symptoms
KW  - large population
Y1  - 2022
U6  - https://doi.org/10.3389/fnut.2022.871669
SN  - 2296-861X
VL  - 9
PB  - Frontiers Media
CY  - Lausanne
ER  - 
TY  - JOUR
A1  - Wardelmann, Kristina
A1  - Rath, Michaela
A1  - Castro, José Pedro
A1  - Blümel, Sabine
A1  - Schell, Mareike
A1  - Hauffe, Robert
A1  - Schumacher, Fabian
A1  - Flore, Tanina
A1  - Ritter, Katrin
A1  - Wernitz, Andreas
A1  - Hosoi, Toru
A1  - Ozawa, Koichiro
A1  - Kleuser, Burkhard
A1  - Weiß, Jürgen
A1  - Schürmann, Annette
A1  - Kleinridders, André
T1  - Central acting Hsp10 regulates mitochondrial function, fatty acid metabolism and insulin sensitivity in the hypothalamus
JF  - Antioxidants
N2  - Mitochondria are critical for hypothalamic function and regulators of metabolism. Hypothalamic mitochondrial dysfunction with decreased mitochondrial chaperone expression is present in type 2 diabetes (T2D). Recently, we demonstrated that a dysregulated mitochondrial stress response (MSR) with reduced chaperone expression in the hypothalamus is an early event in obesity development due to insufficient insulin signaling. Although insulin activates this response and improves metabolism, the metabolic impact of one of its members, the mitochondrial chaperone heat shock protein 10 (Hsp10), is unknown. Thus, we hypothesized that a reduction of Hsp10 in hypothalamic neurons will impair mitochondrial function and impact brain insulin action. Therefore, we investigated the role of chaperone Hsp10 by introducing a lentiviral-mediated Hsp10 knockdown (KD) in the hypothalamic cell line CLU-183 and in the arcuate nucleus (ARC) of C57BL/6N male mice. We analyzed mitochondrial function and insulin signaling utilizing qPCR, Western blot, XF96 Analyzer, immunohistochemistry, and microscopy techniques. We show that Hsp10 expression is reduced in T2D mice brains and regulated by leptin in vitro. Hsp10 KD in hypothalamic cells induced mitochondrial dysfunction with altered fatty acid metabolism and increased mitochondria-specific oxidative stress resulting in neuronal insulin resistance. Consequently, the reduction of Hsp10 in the ARC of C57BL/6N mice caused hypothalamic insulin resistance with acute liver insulin resistance.
KW  - brain insulin signaling
KW  - mitochondria
KW  - oxidative stress
KW  - fatty acid metabolism
Y1  - 2021
U6  - https://doi.org/10.3390/antiox10050711
SN  - 2076-3921
VL  - 10
IS  - 5
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Wilhelmi, Ilka
A1  - Neumann, Alexander
A1  - Jähnert, Markus
A1  - Ouni, Meriem
A1  - Schürmann, Annette
T1  - Enriched alternative splicing in islets of diabetes-susceptible mice
JF  - International journal of molecular sciences
N2  - Dysfunctional islets of Langerhans are a hallmark of type 2 diabetes (T2D). We hypothesize that differences in islet gene expression alternative splicing which can contribute to altered protein function also participate in islet dysfunction. RNA sequencing (RNAseq) data from islets of obese diabetes-resistant and diabetes-susceptible mice were analyzed for alternative splicing and its putative genetic and epigenetic modulators. We focused on the expression levels of chromatin modifiers and SNPs in regulatory sequences. We identified alternative splicing events in islets of diabetes-susceptible mice amongst others in genes linked to insulin secretion, endocytosis or ubiquitin-mediated proteolysis pathways. The expression pattern of 54 histones and chromatin modifiers, which may modulate splicing, were markedly downregulated in islets of diabetic animals. Furthermore, diabetes-susceptible mice carry SNPs in RNA-binding protein motifs and in splice sites potentially responsible for alternative splicing events. They also exhibit a larger exon skipping rate, e.g., in the diabetes gene Abcc8, which might affect protein function. Expression of the neuronal splicing factor Srrm4 which mediates inclusion of microexons in mRNA transcripts was markedly lower in islets of diabetes-prone compared to diabetes-resistant mice, correlating with a preferential skipping of SRRM4 target exons. The repression of Srrm4 expression is presumably mediated via a higher expression of miR-326-3p and miR-3547-3p in islets of diabetic mice. Thus, our study suggests that an altered splicing pattern in islets of diabetes-susceptible mice may contribute to an elevated T2D risk.
KW  - alternative splicing
KW  - epigenetic
KW  - MicroRNA
KW  - RNAseq
KW  - diabetes
KW  - beta-cell
KW  - failure
Y1  - 2021
U6  - https://doi.org/10.3390/ijms22168597
SN  - 1422-0067
VL  - 22
IS  - 16
PB  - Molecular Diversity Preservation International
CY  - Basel
ER  - 
TY  - JOUR
A1  - Tchewonpi Sagu, Sorel
A1  - Landgräber, Eva
A1  - Henkel, Ina M.
A1  - Huschek, Gerd
A1  - Homann, Thomas
A1  - Bußler, Sara
A1  - Schlüter, Oliver
A1  - Rawel, Harshadrai Manilal
T1  - Effect of cereal α-amylase/trypsin inhibitors on developmental characteristics and abundance of digestive enzymes of mealworm larvae (Tenebrio molitor L.)
JF  - Insects : open access journal
N2  - The objective of this work was to investigate the potential effect of cereal α-amylase/trypsin inhibitors (ATIs) on growth parameters and selective digestive enzymes of Tenebrio molitor L. larvae. The approach consisted of feeding the larvae with wheat, sorghum and rice meals containing different levels and composition of α-amylase/trypsin inhibitors. The developmental and biochemical characteristics of the larvae were assessed over feeding periods of 5 h, 5 days and 10 days, and the relative abundance of α-amylase and selected proteases in larvae were determined using liquid chromatography tandem mass spectrometry. Overall, weight gains ranged from 21% to 42% after five days of feeding. The larval death rate significantly increased in all groups after 10 days of feeding (p < 0.05), whereas the pupation rate was about 25% among larvae fed with rice (Oryza sativa L.) and Siyazan/Esperya wheat meals, and only 8% and 14% among those fed with Damougari and S35 sorghum meals. As determined using the Lowry method, the protein contents of the sodium phosphate extracts ranged from 7.80 ± 0.09 to 9.42 ± 0.19 mg/mL and those of the ammonium bicarbonate/urea reached 19.78 ± 0.16 to 37.47 ± 1.38 mg/mL. The total protein contents of the larvae according to the Kjeldahl method ranged from 44.0 and 49.9 g/100 g. The relative abundance of α-amylase, CLIP domain-containing serine protease, modular serine protease zymogen and C1 family cathepsin significantly decreased in the larvae, whereas dipeptidylpeptidase I and chymotrypsin increased within the first hours after feeding (p < 0.05). Trypsin content was found to be constant independently of time or feed material. Finally, based on the results we obtained, it was difficult to substantively draw conclusions on the likely effects of meal ATI composition on larval developmental characteristics, but their effects on the digestive enzyme expression remain relevant.
KW  - growth behavior
KW  - Tenebrio molitor larvae
KW  - feeding
KW  - cereal meals
KW  - α-amylase
KW  - digestive enzymes quantification
KW  - LC-MS/MS
KW  - trypsin inhibitors
Y1  - 2021
U6  - https://doi.org/10.3390/insects12050454
SN  - 2075-4450
VL  - 12
IS  - 5
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Ruszkiewicz, Joanna
A1  - Endig, Lisa
A1  - Güver, Ebru
A1  - Bürkle, Alexander
A1  - Mangerich, Aswin
T1  - Life-cycle-dependent toxicities of mono- and bifunctional alkylating agents in the 3R-compliant model organism C. elegans
JF  - Cells : open access journal
N2  - Caenorhabditis elegans (C. elegans) is gaining recognition and importance as an organismic model for toxicity testing in line with the 3Rs principle (replace, reduce, refine). In this study, we explored the use of C. elegans to examine the toxicities of alkylating sulphur mustard analogues, specifically the monofunctional agent 2-chloroethyl-ethyl sulphide (CEES) and the bifunctional, crosslinking agent mechlorethamine (HN2). We exposed wild-type worms at different life cycle stages (from larvae L1 to adulthood day 10) to CEES or HN2 and scored their viability 24 h later. The susceptibility of C. elegans to CEES and HN2 paralleled that of human cells, with HN2 exhibiting higher toxicity than CEES, reflected in LC50 values in the high µM to low mM range. Importantly, the effects were dependent on the worms’ developmental stage as well as organismic age: the highest susceptibility was observed in L1, whereas the lowest was observed in L4 worms. In adult worms, susceptibility to alkylating agents increased with advanced age, especially to HN2. To examine reproductive effects, L4 worms were exposed to CEES and HN2, and both the offspring and the percentage of unhatched eggs were assessed. Moreover, germline apoptosis was assessed by using ced-1p::GFP (MD701) worms. In contrast to concentrations that elicited low toxicities to L4 worms, CEES and HN2 were highly toxic to germline cells, manifesting as increased germline apoptosis as well as reduced offspring number and percentage of eggs hatched. Again, HN2 exhibited stronger effects than CEES. Compound specificity was also evident in toxicities to dopaminergic neurons–HN2 exposure affected expression of dopamine transporter DAT-1 (strain BY200) at lower concentrations than CEES, suggesting a higher neurotoxic effect. Mechanistically, nicotinamide adenine dinucleotide (NAD+) has been linked to mustard agent toxicities. Therefore, the NAD+-dependent system was investigated in the response to CEES and HN2 treatment. Overall NAD+ levels in worm extracts were revealed to be largely resistant to mustard exposure except for high concentrations, which lowered the NAD+ levels in L4 worms 24 h post-treatment. Interestingly, however, mutant worms lacking components of NAD+-dependent pathways involved in genome maintenance, namely pme-2, parg-2, and sirt-2.1 showed a higher and compound-specific susceptibility, indicating an active role of NAD+ in genotoxic stress response. In conclusion, the present results demonstrate that C. elegans represents an attractive model to study the toxicology of alkylating agents, which supports its use in mechanistic as well as intervention studies with major strength in the possibility to analyze toxicities at different life cycle stages.
KW  - C. elegans
KW  - alkylating agents
KW  - mustards
KW  - life cycle toxicities
KW  - neurotoxicity
KW  - NAD+
Y1  - 2023
U6  - https://doi.org/10.3390/cells12232728
SN  - 2073-4409
VL  - 12
IS  - 23
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Jonas, Wenke
A1  - Schwerbel, Kristin
A1  - Zellner, Lisa
A1  - Jähnert, Markus
A1  - Gottmann, Pascal
A1  - Schürmann, Annette
T1  - Alterations of lipid profile in livers with impaired lipophagy
JF  - International journal of molecular sciences
N2  - Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver. 
Various mechanisms such as an increased uptake in fatty acids or de novo synthesis contribute to the development of steatosis and progression to more severe stages. Furthermore, it has been shown that impaired lipophagy, the degradation of lipids by autophagic processes, contributes to NAFLD. 
Through an unbiased lipidome analysis of mouse livers in a genetic model of impaired lipophagy, we aimed to determine the resulting alterations in the lipidome. Observed changes overlap with those of the human disease. 
Overall, the entire lipid content and in particular the triacylglycerol concentration increased under conditions of impaired lipophagy. 
In addition, we detected a reduction in long-chain polyunsaturated fatty acids (PUFAs) and an increased ratio of n-6 PUFAs to n-3 PUFAs, which was due to the depletion of n-3 PUFAs. 
Although the abundance of major phospholipid classes was reduced, the ratio of phosphatidylcholines to phosphatidylethanolamines was not affected. In conclusion, this study demonstrates that impaired lipophagy contributes to the pathology of NAFLD and is associated with an altered lipid profile. 
However, the lipid pattern does not appear to be specific for lipophagic alterations, as it resembles mainly that described in relation to fatty liver disease.
KW  - non-alcoholic fatty liver disease
KW  - lipophagy
KW  - lipidomics
KW  - fatty acid profile
KW  - long-chain polyunsaturated fatty acids
Y1  - 2022
U6  - https://doi.org/10.3390/ijms231911863
SN  - 1422-0067
VL  - 23
IS  - 19
PB  - MDPI
CY  - Basel
ER  - 
TY  - JOUR
A1  - Huschek, Gerd
A1  - Rawel, Harshadrai M.
A1  - Schweikert, Torsten
A1  - Henkel-Oberländer, Janin
A1  - Sagu Tchewonpi, Sorel
T1  - Characterization and optimization of microwave-assisted extraction of B-phycoerythrin from Porphyridium purpureum using response surface methodology and Doehlert design
JF  - Bioresource Technology Reports
N2  - Microalgae are one of the most promising food source of the future. 
Nowadays, extracts of high-value active substances of biomass are business aims for the development of food additives in personalized nutrition, in cosmetics and pharmaceuticals. 
A new-patented vertical farming cultivation technology was used for production of Porphyridium purpureum. In this work, microwave assisted extraction was used to extract B-phycoerythrin from Porphyridium purpureum biomass. 
Response surface methodology was implemented for optimization. 
Numerical optimization established the best point of the experimental domain (biomass/solvent of 16.8 mg/mL, time of 172 s, and temperature of 30 degrees C) with a desirability value of 0.82. 
Corresponding experimental responses values of 7.2 mg, 8.5 % and 13,961 PA/mu g biomass were obtained for extracted proteins, extraction yield and extracted B-phycoerythrin, respectively. 
Final freeze-dried product indicated protein content of 55 % using Kjeldahl while targeted mass spectrometry analysis revealed that B-phycoerythrin represented 93 % of the total protein.
KW  - porphyridium purpureum
KW  - B-phycoerythrin
KW  - microwave-assisted extraction
KW  - optimization
KW  - mass spectrometry
Y1  - 2022
U6  - https://doi.org/10.1016/j.biteb.2022.101212
SN  - 2589-014X
VL  - 19
PB  - Elsevier
CY  - Amsterdam
ER  - 
TY  - JOUR
A1  - Witt, Barbara
A1  - Stiboller, Michael
A1  - Raschke, Stefanie
A1  - Friese, Sharleen
A1  - Ebert, Franziska
A1  - Schwerdtle, Tanja
T1  - Characterizing effects of excess copper levels in a human astrocytic cell line with focus on oxidative stress markers
JF  - Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements, GMS
N2  - Background: Being an essential trace element, copper is involved in diverse physiological processes. However, excess levels might lead to adverse effects. Disrupted copper homeostasis, particularly in the brain, has been associated with human diseases including the neurodegenerative disorders Wilson and Alzheimer?s disease. In this context, astrocytes play an important role in the regulation of the copper homeostasis in the brain and likely in the prevention against neuronal toxicity, consequently pointing them out as a potential target for the neurotoxicity of copper. Major toxic mechanisms are discussed to be directed against mitochondria probably via oxidative stress. However, the toxic potential and mode of action of copper in astrocytes is poorly understood, so far. Methods: In this study, excess copper levels affecting human astrocytic cell model and their involvement in the neurotoxic mode of action of copper, as well as, effects on the homeostasis of other trace elements (Mn, Fe, Ca and Mg) were investigated. Results: Copper induced substantial cytotoxic effects in the human astrocytic cell line following 48 h incubation (EC30: 250 ?M) and affected mitochondrial function, as observed via reduction of mitochondrial membrane potential and increased ROS production, likely originating from mitochondria. Moreover, cellular GSH metabolism was altered as well. Interestingly, not only cellular copper levels were affected, but also the homeostasis of other elements (Ca, Fe and Mn) were disrupted. Conclusion: One potential toxic mode of action of copper seems to be effects on the mitochondria along with induction of oxidative stress in the human astrocytic cell model. Moreover, excess copper levels seem to interact with the homeostasis of other essential elements such as Ca, Fe and Mn. Disrupted element homeostasis might also contribute to the induction of oxidative stress, likely involved in the onset and progression of neurodegenerative disorders. These insights in the toxic mechanisms will help to develop ideas and approaches for therapeutic strategies against copper-mediated diseases.
KW  - Copper
KW  - Astrocytes
KW  - Toxicity
KW  - Mitochondria
KW  - ROS
KW  - Trace elements
Y1  - 2021
U6  - https://doi.org/10.1016/j.jtemb.2021.126711
SN  - 1878-3252
VL  - 65
PB  - Elsevier
CY  - München
ER  - 
TY  - JOUR
A1  - Baesler, Jessica
A1  - Michaelis, Vivien
A1  - Stiboller, Michael
A1  - Haase, Hajo
A1  - Aschner, Michael
A1  - Schwerdtle, Tanja
A1  - Sturzenbaum, Stephen R.
A1  - Bornhorst, Julia
T1  - Nutritive manganese and zinc overdosing in aging c. elegans result in a metallothionein-mediated alteration in metal homeostasis
JF  - Molecular Nutrition and Food Research
N2  - Manganese (Mn) and zinc (Zn) are not only essential trace elements, but also potential exogenous risk factors for various diseases. Since the disturbed homeostasis of single metals can result in detrimental health effects, concerns have emerged regarding the consequences of excessive exposures to multiple metals, either via nutritional supplementation or parenteral nutrition. This study focuses on Mn-Zn-interactions in the nematode Caenorhabditis elegans (C. elegans) model, taking into account aspects related to aging and age-dependent neurodegeneration.
KW  - aging
KW  - C. elegans
KW  - homeostasis
KW  - manganese
KW  - zinc
Y1  - 2021
U6  - https://doi.org/10.1002/mnfr.202001176
SN  - 1613-4133
SN  - 1613-4125
VL  - 65
IS  - 8
SP  - 1
EP  - 11
PB  - Wiley-VCH GmbH
CY  - Weinheim
ER  - 
TY  - JOUR
A1  - Xiong, Chan
A1  - Stiboller, Michael
A1  - Glabonjat, Ronald A.
A1  - Rieger, Jaqueline
A1  - Paton, Lhiam
A1  - Francesconi, Kevin A.
T1  - Transport of arsenolipids to the milk of a nursing mother after consuming salmon fish
JF  - Journal of trace elements in medicine and biology
N2  - Objective: 
We address two questions relevant to infants' exposure to potentially toxic arsenolipids, namely, are the arsenolipids naturally present in fish transported intact to a mother's milk, and what is the efficiency of this transport.

Methods: 
We investigated the transport of arsenolipids and other arsenic species present in fish to mother's milk by analyzing the milk of a single nursing mother at 15 sampling times over a 3-day period after she had consumed a meal of salmon. Total arsenic values were obtained by elemental mass spectrometry, and arsenic species were measured by HPLC coupled to both elemental and molecular mass spectrometry.

Results: 
Total arsenic increased from background levels (0.1 mu g As kg(-1)) to a peak value of 1.72 lig As kg(-1) eight hours after the fish meal. The pattern for arsenolipids was similar to that of total arsenic, increasing from undetectable background levels (< 0.01 mu g As kg(-1)) to a peak after eight hours of 0.45 mu g As kg(-1). Most of the remaining total arsenic in the milk was accounted for by arsenobetaine. The major arsenolipids in the salmon were arsenic hydrocarbons (AsHCs; 55 % of total arsenolipids), and these compounds were also the dominant arsenolipids in the milk where they contributed over 90 % of the total arsenolipids. 

Conclusions:
Our study has shown that ca 2-3 % of arsenic hydrocarbons, natural constituents of fish, can be directly transferred unchanged to the milk of a nursing mother. In view of the potential neurotoxicity of AsHCs, the effects of these compounds on the brain developmental stage of infants need to be investigated.
KW  - human milk
KW  - arsenolipids
KW  - salmon fish
KW  - HPLC/ICPMS
KW  - HPLC/HR-ESMS
Y1  - 2020
U6  - https://doi.org/10.1016/j.jtemb.2020.126502
SN  - 0946-672X
VL  - 61
PB  - Elsevier
CY  - München
ER  -